Ligands for ADH: cinchona alkaloids and moderately sized organic substituents linked through a planar aromatic spacer group

ABSTRACT

Osmium-catalyzed methods of addition to an olefin are discussed. In the method of asymmetric dihydroxylation of the present invention, an olefin, a chiral ligand, an organic solvent, an aqueous solution, a base, a ferricyanide salt and an osmium-containing compound are combined. The chiral ligand is an alkaloid or alkaloid derivative linked to an organic substituent of at least 300 daltons molecular weight through a planar aromatic spacer group. The organic substituent can be another alkaloid or alkaloid derivative. With the described chiral ligands, asymmetric dihydroxylation of olefins with high yields and enantiomeric excesses are achieved.

RELATED APPLICATIONS

This is a continuation-in-part (CIP) of U.S. Ser. No. 07/699,183 filedMay 13, 1991, which is a continuation in part of application Ser. No.002,778 filed 23 Apr. 1991, which is a continuation in part of U.S. Ser.No. 07/512,934 filed Apr. 23, 1990, now U.S. Pat. No. 5,126,494 issuedJun. 30, 1992, which is a continuation in part of U.S. Ser. No.07/250,378 filed Sep. 28, 1988, now U.S. Pat. No. 4,965,364, which is acontinuation in part of U.S. Ser. No. 07/159,068, filed Feb. 23, 1988,now U.S. Pat. No. 4,871,855, which is a continuation in part of U.S.Ser. No. 142,692, filed Jan. 11, 1988, now abandoned; all of the aboveare hereby incorporated by reference herein.

BACKGROUND

In nature, the organic constituents of animals, microorganisms andplants are made up of chiral molecules, or molecules which exhibithandedness. Enantiomers are stereoisomers or chiral molecules whoseconfigurations (arrangements of constituent atoms) are nonsuperimposedmirror images of each other; absolute configurations at chiral centersare determined by a set of rules by which a priority is assigned to eachsubstituent and are designated R and S. The physical properties ofenantiomers are identical, except for the direction in which they rotatethe plane of polarized light: one enantiomer rotates plane-polarizedlight to the right and the other enantiomer rotates it to the left.However, the magnitude of the rotation caused by each is the same.

The chemical properties of enantiomers are also identical, with theexception of their interactions with optically active reagents.Optically active reagents interact with enantiomers at different rates,resulting in reaction rates which may vary greatly and, in some cases,at such different rates that reaction with one enantiomer or isomer doesnot occur. This is particularly evident in biological systems, in whichstereochemical specificity is the rule because enzymes (biologicalcatalysts) and most of the substrates on which they act are opticallyactive.

A mixture which includes equal quantities of both enantiomers is aracemate (or racemic modification). A racemate is optically inactive, asa result of the fact that the rotation of polarized light caused by amolecule of one isomer is equal to and in the opposite direction fromthe rotation caused by a molecule of its enantiomer. Racemates, notoptically active compounds, are the products of most syntheticprocedures. Because of the identity of most physical characteristics ofenantiomers, they cannot be separated by such commonly used methods asfractional distillation (because they have identical boiling points),fractional crystallization (because they are equally soluble in asolvent, unless it is optically active) and chromatography (because theyare held equally tightly on a given adsorbent, unless it is opticallyactive). As a result, resolution of a racemic mixture into enantiomersis not easily accomplished and can be costly and time consuming.

Recently, there has been growing interest in the synthesis of chiralcompounds because of the growing demand for complex organic molecules ofhigh optical purity, such as insect hormones and pheromones,prostaglandins, antitumor compounds, and other drugs. This is aparticularly critical consideration, for example, for drugs, because inliving systems, it often happens that one enantiomer functionseffectively and the other enantiomer has no biological activity and/orinterferes with the biological function of the first enantiomer.

In nature, the enzyme catalyst involved in a given chemical reactionensures that the reaction proceeds asymmetrically, producing only thecorrect enantiomer (i.e., the enantiomer which is biologically orphysiologically functional). This is not the case in laboratorysynthesis, however, and, despite the interest in and energy expended indeveloping methods by which asymmetric production of a desired chiralmolecule (e g., of a selected enantiomer) can be carried out, there hasbeen only limited success.

In addition to resolving the desired molecule from a racemate of the twoenantiomers, it is possible, for example, to produce selected asymmetricmolecules by the chiral pool or template method, in which the selectedasymmetric molecule is "built" from pre-existing, naturally-occurringasymmetric molecules. Asymmetric homogeneous hydrogenation andasymmetric epoxidation have also been used to produce chiral molecules.Asymmetric hydrogenation is seen as the first manmade reaction to mimicnaturally-occurring asymmetric reactions. Sharpless, K. B., Chemisry inBritain, January 1986, pp 38-44; Mosher. H. S. and J. D. Morrison,Science, 221:1013-1019 (1983); Maugh, T. H., Science, 221:351-354(1983); Stinson, S., Chemistry and Engineering News, :24 (Jun. 2, 1986).

Presently-available methods of asymmetric synthesis are limited in theirapplicability, however. Efficient catalytic asymmetric synthesisreactions are very rare; and they usually require a directing group andthus are substrate limited. Because such reactions are rare andchirality can be exceptionally important in drugs, pheromones and otherbiologically functional compositions, a catalytic method of asymmetricdihydroxylation would be very valuable. In addition, manynaturally-occurring products are dihydroxylated or can be easily derivedfrom a corresponding vicinal diol derivative.

SUMMARY OF THE INVENTION

Olefins or alkenes with or without proximal heteroatom-containingfunctional groups, are asymmetrically dihydroxylated, oxyaminated ordiaminated using an osmium-catalyzed process which is the subject of thepresent invention. Chiral ligands which are novel alkaloid derivatives,particularly quinidine derivatives, dihydroquinidine derivatives,quinine derivatives, dihydroquinine derivatives or salts thereof, usefulin the method of the present invention are also the subject of thepresent invention.

One embodiment of the invention pertains to compositions that can beused as chiral ligands in the asymmetric dihydroxylation of olefins.These compositions have three moieties covalently linked together in aprescribed configuration. One moiety is an alkaloid or alkaloidderivative. A second moiety is an organic substituent whose molecularweight is at least 300 daltons. In a preferred embodiment, the organicsubstituent is an alkaloid or alkaloid derivative, often identical tothe substance that constitutes the first moiety. The first and secondmoieties are connected to each other through an intervening planararomatic spacer group. This spacer group is covalently bonded to boththe alkaloid or alkaloid derivative and the organic substituent.Additionally, the spacer group separates the first and second moietiesfrom each other.

Another embodiment of the invention pertains to asymmetricdihydroxylation of olefins by reactions that utilize the chiral ligandsdescribed in the previous paragraph. In these reactions, an olefin, anorganic solvent, an aqueous solution, a base, an osmium-containingcatalyst, a ferricyanide salt and a chiral ligand are combined underconditions appropriate for asymmetric addition to occur. The chiralligand (termed a chiral auxiliary) is an alkaloid or alkaloid derivativeand an organic substituent of at least 300 daltons molecular weightlinked together through a planar aromatic spacer group. In a preferredembodiment, the chiral auxiliary, organic solvent, aqueous solution,base, osmium-containing catalyst and ferricyanide salt are combined, theolefin is added and the resulting combination is maintained underconditions appropriate for asymmetric dihydroxylation of the olefin tooccur.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic representation of asymmetric dihydroxylation vialigand-accelerated catalysis which is carried out by the method of thepresent invention.

FIG. 2 is a schematic representation of asymmetric catalyticoxyamination of stilbene which is carried out by the method of thepresent invention.

FIG. 3 is a plot of amine concentration vs second-order-rate constant kfor the catalytic cis-dihydroxylation of styrene. At point a, no aminehas been added. Point a thus represents the rate of the catalyticprocess in the absence of added amine ligands. Line b represents therate of the catalytic process in the presence of varying amounts ofquinuclidine, a ligand which substantially retards catalysis. Line crepresents the rate of the catalytic process in the presence of thedihydroquinidine benzoate derivative 1 represented in FIG. 1. K isdefined as K_(obs) /[OsO₄ ]_(o) where rate=-d[styrene]/dt=K_(obs)[styrene]. Conditions: 25° C., [OsO₄ ]_(o) =4×10⁻⁴ M, [NMO]_(o) =0.2M[styrene]_(o) =0.1M.

FIG. 4 is a schematic representation of a proposed mechanism ofcatalytic olefin dihydroxylation. This scheme shows two diol-producingcycles believed to be involved in the ligand-accelerated catalysis ofthe present invention. Formula 1 represents an alkaloid-osmium complex;formula 2 represents a monoglycolate ester; formula 3 represents anosmium(VIII)trioxoglycolate complex; formula 4 represents a bisglycolateosmium ester; and formula 5 represents a dioxobisglycolate.

DETAILED DESCRIPTION OF THE INVENTION

Asymmetric epoxidation has been the subject of much research for morethan ten years. Earlier work demonstrated that the titanium-tartrateepoxidation catalyst is actually a complex mixture of epoxidationcatalysts in dynamic equilibrium with each other and that the mainspecies present (i.e., the 2:2 structure) is the best catalyst (i.e.,about six times more active than titanium isopropoxide hearing notartrate). This work also showed that this rate advantage is essentialto the method's success because it ensures that the catalysis ischanneled through a chiral ligand-bearing species.

The reaction of osmium tetroxide (OsO₄) with olefins is a highlyselective and reliable organic transformation. It has long been knownthat this reaction is accelerated by nucleophilic ligands. Criegee, R.Justus Liebigs Ann. Chem., 522:75 (1936); Criegee, R. et al., JustusLiebigs Ann. Chem., 550:99 (1942); VanRheenen et al., Tetrahedron Lett.,1973 (1976). It has now been shown that a highly effectiveosmium-catalyzed process can be used to replace previously knownmethods, such as the stoichiometric asymmetric osmylation method.Hentges, S. G. and K. B. Sharpless, Journal of the American ChemicalSociety, 102:4263 (1980). The method of the present invention results inasymmetric induction and enhancement of reaction rate by binding of aselected ligand. Through the use of the ligand-accelerated catalyticmethod of the present invention, asymmetric dihydroxylation, asymmetricdiamination or asymmetric oxyamination can be effected.

As a result of this method, two hydroxyl groups are stereospecificallyintroduced into (imbedded in) a hydrocarbon framework, resulting in cisvicinal dihydroxylation. The new catalytic method of the presentinvention achieves substantially improved rates and turnover numbers(when compared with previously-available methods), as well as usefullevels of asymmetric induction. In addition, because of the improvedreaction rates and turnover numbers, less osmium catalyst is needed inthe method of the present invention than in previously-known methods. Asa result, the expense and the possible toxicity problem associated withpreviously-known methods are reduced. Furthermore, the invention allowsthe recovery and reuse of osmium, which reduces the cost of the process.

The method of the present invention is exemplified below with particularreference to its use in the asymmetric dihydroxylation of E-stilbene (C₆H₅ CH:CHC₆ H₅) and trans-3-hexene (CH₃ CH₂ CH:CHCH₂ CH₃). The method canbe generally described as presented below and that description andsubsequent exemplification not only demonstrate the dramatic andunexpected results of ligand-accelerated catalysis, but also makeevident the simplicity and effectiveness of the method.

The asymmetric dihydroxylation method of the present invention isrepresented by the scheme illustrated in FIG. 1. According to the methodof the present invention, asymmetric dihydroxylation of a selectedolefin is effected as a result of ligand-accelerated catalysis. That is,according to the method, a selected olefin is combined, underappropriate conditions, with a selected chiral ligand (which in generalwill be a chiral substituted quinuclidine), an organic solvent, water,an oxidant and osmium tetroxide and, optionally, a compound whichpromotes hydrolysis of the products from the osmium. Acids or bases canbe used for this purpose. In one embodiment, a selected olefin, a chiralligand, an organic solvent, water and an oxidant are combined; after theolefin and other components are combined, OsO₄ is added. The resultingcombination is maintained under conditions (e.g., temperature,agitation, etc.) conducive for dihydroxylation of the olefin to occur.Alternatively, the olefin, organic solvent, chiral ligand, water andOsO₄ are combined and the oxidant added to the resulting combination.These additions can occur very close in time (i.e., sequentially orsimultaneously).

In one embodiment of the present invention, components of the reactionmixture are combined, to form an initial reaction combination, andolefin is added slowly to it, generally with frequent or constantagitation, such as stirring. In this embodiment, designated the "slowaddition" method, organic solvent, chiral ligand, water, OsO₄ and theoxidant are combined. The olefin can then be slowly added to the otherreactants. It is important that agitation, preferably stirring, beapplied during the olefin addition. Surprisingly, for many, if not mostolefins, slow addition of the olefin to the initial combination resultsin much better enantiomeric excess (ee), and a faster race of reactionthan the above-described method (i.e., that in which all the olefin ispresent at the beginning of the reaction). The beneficial effects (i.e..higher ee's) of slow olefin addition are shown in Table 5 (Column 6). Aparticular advantage of this slow-addition method is that the scope ofthe types of olefins to which the asymmetric dihydroxylation method canbe applied is greatly broadened. That is, it can be applied to simplehydrocarbon olefins bearing no aromatic substituents, or otherfunctional groups. In this process, the olefin is added slowly (e.g.,over time), as necessary to maximize ee. This method is particularlyvaluable because it results in higher ee's and faster reaction times.

In another embodiment of the present method, the chiral ligands areimmobilized or incorporated into a polymer, thereby immobilizing theligands. Both monomers and polymers of alkaloid ligands can beimmobilized. The immobilized ligands form a complex with the osmiumcatalyst, which results in formation of an osmium catalyst complex whichcan be recovered after the reaction. The OsO₄ -polymer complex isrecoverable and can be used for iterative processes without washing orother treatment. The complex can be recovered, for example, byfiltration or centrifugation. By employing alkaloid derivatives,heterogeneous catalytic asymmetric dihydroxylation is achieved with goodto excellent enantioselectivities in the dihydroxylation of olefins.

Alternatively, alkaloid polymers can be used as ligands. Alkaloidpolymers which can be used are described, for example, by Kobayashi andIwai in Tetrahedron Letters, 21:2167-2170 (1980) and Polymer Journal,13(3) 263-271 (1981); by vonHermann and Wynberg in Helvetica ChimicaActa, 60:2208-2212 (1977); and by Hodge et al., J. Chem. Soc. PerkinTrans. I, (1983) pp. 2205-2209. Both alkaloid polymer liganus andimmobilized ligands form a complex with the osmium in situ. The term"polymeric", as used herein is meant to include monomers or polymers ofalkaloid ligands which are chemically bonded or attached to a polymercarrier, such that the ligand remains attached under the conditions ofthe reaction, or ligands which are copolymerized with one or moremonomers (e.g., acrylonitrile) to form a co-polymer in which thealkaloid is incorporated into the polymer, or alkaloid polymers asdescribed above, which are not immobilized or copolymerized with anotherpolymer or other carrier.

Industrial scale syntheses of optically active vicinal diols arepossible using polymeric ligands. The convenience and economy of theprocess is enhanced by recycling the alkaloid-OsO₄ complex. Thisembodiment of the present method allows efficient heterogeneousasymmetric dihydroxylation utilizing polymeric or immobilized cinchonaalkaloid derivatives.

Polymeric cinchona alkaloids which are useful in the present method canbe prepared by art-recognized techniques. See, for example, Grubhoferand Schleith, Naturwissenschaften, 40:508 (1953); Yamauchi et al., Bull.Chem. Soc. Jpn., 44:3186 (1971); Yamauchi et al., J. Macromal. Sci.Chem., A10:981 (1976). A number of different types of polymers thatincorporate dihydroquinidine or dihydroquinine derivatives can be usedin this process. These polymers include: (a) co-polymers of cinchonaalkaloid derivatives with co-polymerizing reagents, such as vinylchloride, styrene, acrylamide, acrylonitrile, or acrylic or methacrylicacid esters; (b) cross-linked polymers of cinchona alkaloid derivativeswith cross-linking reagents, such as 1,4-divinylbenzene, ethylene glycolbismethacrylate; and (c) cinchona alkaloid derivatives covalently linkedto polysiloxanes. The connecting point of the polymer backbone to thealkaloid derivative can be at C(10), C(11), C(9)-O,N(1'), or C(6')-O asshown below for both quinidine and quinine derivatives. Table 3 showsthe examples of the monomeric alkaloid derivatives which can beincorporated in the polymer system.

For example, a polymer binding dihydroquinidine was prepared bycopolymerizing 9-(10-undecenoyl)dihydroquinidine in the presence ofacrylonitrile (5 eq); a 13% yield was obtained exhibiting 4% alkaloidincorporation. This polymer, an acrylonitrile co-polymer of9-(10-undecenoyl)-10,11-dihydroquinidine, is shown as polymer 4 in Table1, below. Three other polymers, an acrylonitrile co-polymer of9-(4-chlorobenzoyloxy)quinine, (polymer 1, Table 3) an acrylonitrileco-polymer of11-[2-acryloyloxy)ethylsulfinyl]-9-(4-chlorobenzoyloxy)--10,11-dihydroquinine(polymer 2, Table 1) and an acrylonitrile co-polymer of11-[2-acryloyloxy)-ethylsulfonyl]-9-(N,N-dimethylcarbamoyl)-10,11-dihydroquinidine,(polymer 3, Table 1) were prepared according to the procedures ofInaguki et al., or slightly modified versions of this procedure. See,Inaguki et al., Bull. Chem. Soc. Jpn., 60:4121 (1987). Using thesepolymers, the asymmetric dihydroxylation of trans-stilbene was carriedout. The results are summarized in Table 1. Good to excellent asymmetricinduction and reasonable reaction rates were observed. As shown in Table1, reaction with polymer 2 exhibited the highest degree of asymmetricinduction. The activity of the OsO₄ -polymer complex is preserved afterthe reaction, thus allowing repetitive use of the complex. This reactioncan be carried out with terminal and aliphatically substituted olefinsto show good yields and enantioselectivities (for example, styrene withpolymer 2, 60% ee, 68% yield and ethyltrans-2-octenoate with polymer 3,60% ee, 85% yield) and the same process can be applied to a variety ofdifferent olefins.

                                      TABLE 1                                     __________________________________________________________________________    Heterogeneous Catalytic Asymmetric                                            Dihydroxylation of trans-Stilbene Using Variuos Polymeric                     Alkaloids                                                                      ##STR1##                                                                      ##STR2##                                                                                     Secondary                                                                           Reaction                                                                           Reaction                                           Entry                                                                             Polymers                                                                           O.sub.s O.sub.4                                                                      Oxidant                                                                             Temp Time Yield (%)                                                                           ee (%)                                  __________________________________________________________________________    1   1    1  mol %                                                                             NMO   rt    7d  68    --                                      2   2    1  mol %                                                                             NNO   10° C.                                                                       2-3d                                                                              81-87 85-93.sup.b                             3   2    1  mol %                                                                             NMO   rt   24 h 81    82                                      4   2    --.sup.c                                                                             NMO   rt   36 h 75    78                                      5   3    1  mol %                                                                             NMO    0° C.                                                                      48 h 85    80                                      6   3    1.25                                                                             mol %                                                                             K.sub.3 Fe(CN).sub.6                                                                rt   18 h 96    87                                      7   4    1  mol %                                                                             NMO   10° C.                                                                      48 h 87    82                                      8   4    1.25                                                                             mol %                                                                             K.sub.3 Fe(CN).sub.6                                                                rt   48 h 91    86                                      __________________________________________________________________________     .sup.a General procedure is set out in detail in Example 14. With             Nmethylmorpholine-N-oxide (NMO) acetone/water (10/1, v/v) was the solvent     and ferricyanide tertbutyl alcohol/water (1/1, v/v) was used as solvent.      .sup.b Results vary slightly depending on different batches of polymer 2.     .sup.c Reaction was carried out with polymer 2 which had been used in         entry 3 without further addition of O.sub.s O.sub.4.                     

In another embodiment of the present method, an additive whichaccelerates hydrolysis of the osmate ester intermediates can,optionally, be added to the reaction combination. These additives can beacids or bases, for example. Bases are preferred for this purpose. Forexample, soluble, carboxylic acid salts with organic-solubilizingcounter-ions (e.g., tetraalkyl ammonium ions) are useful. Carboxylatesalts which are preferred in the present reaction are soluble in organicmedia and in organic/aqueous co-solvent systems. For example, tetraethylammonium acetate has been shown to enhance the reaction rate and ee ofsome olefins (Table 5). The additive does not replace the alkaioid inthe reaction. Compounds which can be used includebenzyltrimethylammoniumacetate, tetramethylammonium acetate andtetraethylammonium acetate. However, other oxyanion compounds (e.g.,sulfonates, carbonates, borates or phosphates) may also be useful inhydrolyzing the osmate ester intermediates. The compound can be added tothe reaction combination of organic solvent, chiral ligand, water andOsO₄ in a reaction vessel before olefin addition. It is important toagitate (e.g.. by stirring) the reaction combination during olefinaddition. The additive can also be added to the reaction combination,described above, wherein all of the olefin is added at the beginning ofthe reaction. In one embodiment, the amount of additive is generallyapproximately 2 equivalents; in general from about 1 to about 4equivalents will be used.

In another embodiment of the present invention, the process can be runin an organic non-polar solvent such as toluene. This embodiment isparticularly useful in the slow addition method. Preferably, acarboxylate compound which accelerates hydrolysis of the osmate esterintermediates (e.g., tetraethyl- or tetramethyl ammonium acetate) isadded. This embodiment is designated the "phase transfer" method. Inthis embodiment olefins which are not soluble, or have limitedsolubility, in mixtures of acetone/water or acetonitrile/water, aredissolved in toluene and then added slowly a mixture of organic solvent,chiral ligand, water and OsO₄. The carboxylate salt serves the dualfunction of solubilizing the acetate ion in the organic phase where itcan promote hydrolysis of the osmate ester, and carrying waterassociated with it into the organic phase, which is essential forhydrolysis. Higher ee's are obtained with many substrates using thismethod.

In a further embodiment of the present invention, a boric acid or aboric acid derivative (R-B(OH)₂, R=alkyl, aryl or OH), such as boricacid itself (i.e., B(OH)₃) or phenylboric acid (i.e., Ph-B(OH)₂), can beadded to the reaction mixture. In the slow addition method, the boricacid is added to the ligand--organic solvent--OsO₄ mixture prior to theaddition of the olefin. The amount of boric acid added is an amountsufficient to form the borate ester of the diol produced in thereaction. Without wishing to be bound by theory, it is believed that theboric acid hydrolyzes the osmium ester and captures the diols which aregenerated in the reaction. Neither water nor a soluble carboxylate suchas tetraalkyl ammonium carboxylate, is required to hydrolyze the osmiumester in the present reactions. Because the presence of water can makethe isolation and recovery of water-soluble diols difficult, theaddition of a boric acid makes isolation of these diols easier.Especially, in the case of an aryl or alkyl boric acid, it is easybecause, in place of the diol, the product is the cyclic borate esterwhich can be subsequently hydrolyzed to the diol. Iwasawa et al.,Chemistry Letters, pp. 1721-1724 (1988). The addition of a boric acid isparticularly useful in the slow addition method.

In another embodiment of the present method, oxidants such as potassiumhexacyanoferrate (III) (potassium ferricyanide, K₃ Fe(CN)₆) is added tothe reaction as a reoxidant. In a preferred embodiment, at least twoequivalents of the oxidant (based on the amount of olefin substrate) isadded to the reaction. It is also preferable that an equivalent amountof a base, such as potassium carbonate (K₂ CO₃), is added in conjunctionwith the reoxidant. High enantioselectivities are obtained in catalyticasymmetric dihydroxylations using K₃ Fe(CN)₆ as the reoxidant.

The use of potassium ferricyanide in a stoichiometric amount as anoxidant for non-asymmetric osmium-catalyzed dihydroxylation of olefinswas reported by Minato, Yamamoto and Tsuji, in J. Org. Chem., 55:766(1990). The addition of K₃ Fe(CN)₆ (in conjunction with the base)results in an improvement in the ability of the Tsuji's catalytic systemto turn over, even in the presence of quinuclidine, a ligand whichstrongly inhibits catalysis when other oxidants are used, e.g.N-methylmorpholine-N-oxide (NMO). In the present embodiment, potassiumferricyanide and potassium carbonate were added to the present cinchonaalkaloid-based asymmetric dihydroxylation process and the outcome wasunexpected (i.e. not just another way to reoxidize the osmium and/orachieve better turnover with difficult substrates). As shown in Table 2,the use of potassium ferricyanide/potassium carbonate in place of NMOleads to across-the-board increases in the level of asymmetric inductionfor most olefins. The first two columns of data shown in Table 2 are forresults employing NMO with and without "slow addition" of olefin,respectively. The third column reveals the results obtained using K₃Fe(CN)₆ with the same substrates and without "slow addition" of theolefin. The improvements of enantioselectivity are great as evidenced bythe fact that the previous results (shown in Table 2) were obtained at0° C. while the ferricyanide experiments were performed at roomtemperature. The ferricyanide reactions can be run at a range oftemperatures, however, depending upon the substrate.

                                      TABLE 2                                     __________________________________________________________________________    Percentage enatiomeric excesses of diols                                      obtained in the asymmetric dihydroxylation of olefins                         under different catalytic conditions using                                    dihydroquinidine p-chlorobenzoate as the chiral ligand.                        ##STR3##                                                                                              NMO.sup.a        K.sub.3 Fe(CN).sub.6.sup.b                                   ee (%)  ee (%)   ee (%)                              entry                                                                            olefins               (slow addition)                                                                       (no slow addition)                                                                     (no slow addition)                  __________________________________________________________________________        ##STR4##             60      56       73                                  2                                                                                 ##STR5##             95      78       99                                  3                                                                                 ##STR6##             86      65       91                                  4                                                                                 ##STR7##             79      76       91                                  5                                                                                 ##STR8##             86      60       95                                  6                                                                                 ##STR9##             69      20       74                                  __________________________________________________________________________     .sup.a Reactions were carried out in acetonewater, 10:1 v/v, at 0°     C.                                                                            .sup.b Reactions were carried out in tertbutyl alcoholwater 1:1 v/v, at       ambient temperature.                                                          In all cases the isolated yield was 85% -95%.                            

The amount of water added to the reaction mixture is an important factorin the present method. The optimum amount of water to be added can bedetermined empirically and, in general, should be that amount whichresults in maximum ee. Generally, approximately 10 to 16 equivalents ofwater can be added, preferably 13 to 14 equivalents should be used.

An olefin of interest can undergo asymmetric dihydroxylation accordingto the present invention. For example, any hydrocarbon containing atleast one carbon-carbon double bond as a functional group can beasymmetrically dihydroxylated according to the subject method. Themethod is applicable to any olefin of interest and is particularly wellsuited to effecting asymmetric dihydroxylation of prochiral olefins(i.e., olefins which can be converted to products exhibiting chiralityor handedness). In the case in which the method of the present inventionis used to asymmetrically dihydroxylate a chiral olefin, one enantiomerwill be more reactive than the other. As a result, it is possible toseparate or kinetically resolve the enantiomorphs. That is, through useof appropriately-selected reactants, it is possible to separate theasymmetrically dihydroxylated product from the unreacted startingmaterial and both the product and the recovered starting material willbe enantiomerically enriched.

The chiral ligand used in the asymmetric dihydroxylation method willgenerally be an alkaloid, or a basic nitrogenous organic compound, whichis generally heterocyclic. The chiral ligand can be a naturallyoccurring compound, a purely synthetic compound or a salt thereof, suchas a hydrochloride salt. The optimum derivative which is used can bedetermined based upon the process conditions for each reaction. Examplesof alkaloids which can be used as the chiral ligand in the asymmetricdihydroxylation method include cinchona alkaloids, such as quinine,quinidine, cinchonine, and cinchonidine. Examples of alkaloidderivatives useful in the method of the present invention are shown inTable 3. As described in detail below, the two cinchona alkaloidsquinine and quinidine act more like enantiomers than like diastereomersin the scheme represented in FIG. 1.

As represented in FIG. 1, and as shown by the results in Table 4,dihydroquinidine derivatives (represented as DHQD) and dihydroquininederivatives (represented as DHQ) have a pseudo-enantiomeric relationshipin the present method (DHQD and DHQ are actually diastereomers). Thatis, they exhibit opposite enantiofacial selection. Such derivatives canbe, for example, esters or ethers, although other forms can be used. Thechoice of derivative depends upon the process. When dihydroquinidine isused as the ligand, delivery of the two hydroxyl groups takes place fromthe top or upper face (as represented in FIG. 1) of the olefin which isbeing dihydroxylated. That is, in this case direct attack of the re- orre,re- face occurs. In contrast, when the dihydroquinine derivative isthe ligand used, the two hydroxyl groups are delivered from the bottomor lower (si- or si,si-face) face of the olefin, again as represented inFIG. 1. This is best illustrated by reference to entries 1, 2 and 5 ofTable 4. As shown, when DHQD (dihydroquinidine esters) is used, theresulting diol has an R or R,R configuration and when ligand 2(dihydroquinine esters) is used, the resulting diol has an S or S,Sconfiguration.

                  TABLE 3                                                         ______________________________________                                        Alkaloid Derivatives                                                           ##STR10##                                                                                Dihydroquinidine                                                  R           Derivative    Yield (%)   % ee                                    ______________________________________                                        3-ClC.sub.6 H.sub.4                                                                       3-chlorobenzoyl                                                                             89          96.5                                    2-MeOC.sub.6 H.sub.4                                                                      2-methoxybenzoyl                                                                            89          96                                      3-MeOC.sub.6 H.sub.4                                                                      3-methoxybenzoyl                                                                            87          96.7                                    2-C.sub.10 H.sub.7                                                                        2-napthoyl    95.4        98.6                                    C.sub.6 H.sub.11                                                                          cyclohexanoyl 90          91                                      4-PhC.sub.6 H.sub.4                                                                       4-phenylbenzoyl                                                                             89          96                                      2,6-(MeO).sub.2 C.sub.6 H.sub.3                                                           2,5-dimethoxy-                                                                              88          92                                                  benzoyl                                                           4-MeOC.sub.6 H.sub.4                                                                      4-methoxyenzoyl                                                                             91          97.6                                    4-ClC.sub.6 H.sub.4                                                                       4-chlorobenzoyl                                                                             93          99                                      2-ClC.sub.6 H.sub.4                                                                       2-chlorobenzoyl                                                                             87          94.4                                    4-NO.sub.2 C.sub.6 H.sub.4                                                                4-nitrobenzoyl                                                                              71          93                                      C.sub.6 H.sub.5                                                                           benzoyl       92          98                                      Me.sub.2 N  dimethyl-     96          95                                                  carbamoyl                                                         Me          acetyl        72          94                                      MeOCH.sub.2 α-methoxyacetyl                                                                       66          93                                      AcOCH.sub.2 α-acetoxyacetyl                                                                       96          82.5                                    Me.sub.3 C  trimethylacetyl                                                                             89          86.5                                    The example below is a phosphoryl derivative and therefore                    differs from the carboxylic acid ester derivatives shown above:               the phosphorus atom is directly bound to the oxygen atom of                   the alkaloid.                                                                 Ph.sub.2 P(O)                                                                             diphenylphosphinic                                                                          69          97.5                                                ester                                                             ______________________________________                                    

                                      TABLE 4                                     __________________________________________________________________________                        ligand; ee.sup.a ;                                        Olefins             confgn. of diol                                           __________________________________________________________________________     ##STR11##          DHQD; 20%, (70%, 10 h); RR DHQ; (60%, 16 h); SS            ##STR12##          DHQD; (70%, 120 h)                                         ##STR13##          DHQD; (69%, 30 h); RR DHQ; (63%, 30 h); SS                 ##STR14##          DHQD; 12%, (46%, 24 h), (76%, 24 h + 1 eq OAc)             ##STR15##          DHQD; 37.5%                                                ##STR16##          DHQD; (46%, 24 h, rt)                                      ##STR17##          DHQD; (40%, 24 h, rt)                                      ##STR18##          DHQD; 46%, (50%, 20 h); R                                  ##STR19##          DHQD; 50%                                                  ##STR20##          DHQD; 40%                                                  ##STR21##          DHQD; 35%, (40%, 12 h)                                     ##STR22##          DHQD; 56%, (61%, 5 h); R  DHQ; 54%; S                      ##STR23##          DHQD; 53%                                                  ##STR24##          DHQD; 65%                                                  ##STR25##          DHQD; 63%                                                  ##STR26##          DHQD; 65%, (86%, 5 h); RR DHQ; 55%, (80%, 5 h); SS         ##STR27##          DHQD; 0-10%                                                ##STR28##          DHQD; 33%; R                                               ##STR29##          DHQD; 34%, (53%, 24 h)                                     ##STR30##          DHQD; 51%                                                  ##STR31##          DHQD; 67%                                                  ##STR32##          DHQD; 40%                                                  ##STR33##          DHQD; 80%; 92% in the presence of 2 eq. OAc; RR DHQ;                          79%; SS                                                    ##STR34##          DHQD; 10%, (78%, 26 h), (81%, 16 h + 1 eq OAc) DHQ;                           (73%, 26 h)                                                ##STR35##          DHQD; 76%; RR                                              ##STR36##          DHQD; 80%                                                  ##STR37##          DHQD; 60%, (78%, 10 h)                                     ##STR38##          DHQD; 20%                                                  ##STR39##          DHQD; (44%, 10 h)                                          ##STR40##          DHQD; 34%                                                  ##STR41##          DHQD; 27%                                                  ##STR42##          DHQD; 38%                                                  ##STR43##          DHQD; 47.4%, (67%, 31 h)                                   ##STR44##          DHQD; 53%                                                  ##STR45##          DHQD; 45%                                                  ##STR46##          DHQD; (52% de, 31 h)                                       ##STR47##          DHQD; (70% de, 42 h)                                       ##STR48##          DHQD; 74.3%                                                ##STR49##          DHQD; (36%, 24 h + OAc, rt)                                ##STR50##          DHQD; 92%                                                  ##STR51##          DHQD; 91%                                                  ##STR52##          DHQD; 80-85%                                               ##STR53##          DHQD; <60%, (80%, slow addition)                           ##STR54##          DHQD; (38%, toluene-water, 24 h + OAc, rt)                 ##STR55##          DHQD; (10%, 24 h, rt)                                      ##STR56##          DHQD; (36%, 24 h + OAc, rt)                                ##STR57##          DHQD; (37%, 12 h + OAc)                                    ##STR58##          DHQD; 27%, (31%, 13 h)                                     ##STR59##          DHQD; (56%, 20 h) (66%, 20 h + OAc)                        ##STR60##          DHQD; (46%, 18 h) (50%, 18 h + OAc)                        ##STR61##          DHQD; 75%, 18 h) (83%, 18 h + OAc)                         ##STR62##          DHQD; (60%, 10 h) (89%, 10 h + OAc)                        ##STR63##          DHQD; (85%, 20 h) (87%, 20 h + OAc)                        ##STR64##          DHQD; (27%, 23 h + OAc)                                    ##STR65##          DHQD; (72%, 23 h) (78%, 23 h + OAc)                       __________________________________________________________________________     .sup.a Enantiomeric excesses in parentheses were obtained with slow           addition of olefin over a period of time indicated and with stirring at       0° C. except otherwise stated. Tetraethylammonium acetate              tetrahydrate were added in some cases as indicated.                      

                                      TABLE 5                                     __________________________________________________________________________    Enantiomeric excesses obtained in the asymmetric dihydroxylation of           olefins under different conditions                                                                    catalytic.sup.b                                                                    catalytic.sup.c                                                                    catalytic.sup.d                             entry                                                                            olefin       stoichiometric.sup.a                                                                  (original)                                                                         (acetate)                                                                          (slow addition)                             __________________________________________________________________________        ##STR66##   61      56   61   60 (5 h)                                    2                                                                                 ##STR67##   87      65   73   86 (5 h)                                    3                                                                                 ##STR68##   79       .sup. 8.sup.e                                                                     52   78 (26 h).sup.f                             4                                                                                 ##STR69##   80      .sup. 12.sup.g                                                                     61   46 (24 h).sup.h  76 (24 h + OAc)            5                                                                                 ##STR70##   69      20   64   70 (10 h)                                   __________________________________________________________________________     .sup.a All stoichiometric reactions were carried out in acetonewater, 10:     v/v, at 0° C. and at a concentration of 0.15M in each reagent.         .sup.b All reactions were carried out at 0° C. according to the        original procedure reported in ref. 1(a).                                     .sup. c All reactions were carried out exactly as described in ref. 1(a)      (i.e. without slow addition) except that 2 eq of Et.sub.4 NOAc4H.sub.2 O      were present.                                                                 .sup.d All reactions were carried out at 0° C. as described in not     2 for trans3-hexene with an alkaloid concentration of 0.25M. The period       for slow addition of the olefin is indicated in parentheses. The ee's         shown in the Table were obtained with dihydroquinidine pchlorobenzoate as     the ligand. Under the same conditions, the pseudoenantiomer,                  dihydroquinine pchlorobenzoate, provides products with ee's 5-10% lower.      In all cases the isolated yield was 85-95%.                                   .sup.e This reaction took 7 days to complete.                                 .sup.f With an addition period of 16 h, ee's of 63 and 65% were obtained      at 0° C. and 20° C., respectively; with the combination of      slow addition over a period of 16 h and the presence of 1 eq of Et.sub.4      NOAc4H.sub.2 O at 0° C., an ee of 81% was realized.                    .sup.g This reaction took 5 days to complete.                                 .sup.k When the reaction was carried out at 20° C. and the olefin      was added over a period of 24 h, an ee of 59% was obtained.              

Because of this face selection rule or phenomenon, it is possible,through use of the present method and the appropriate chiral ligand, topre-determine the absolute configuration of the dihydroxylation product.

As is also evident in Table 4, asymmetric dihydroxylation of a widevariety of olefins has been successfully carried out by means of thepresent invention. Each of the embodiments described results inasymmetric dihydroxylation, and the "slow addition" method isparticularly useful for this purpose. In each of the cases representedin the Table in which absolute configuration was established, the faceselection "rule" (as interpreted with reference to the orientationrepresented in FIG. 1) applied: use of DHQD resulted in attack ordihydroxylation occurring from the top or upper face and use of DHQresulted in attack or dihydroxylation occurring from the bottom or lowerface of the olefin. This resulted, respectively, in formation ofproducts having an R or R,R configuration and products having an S orS,S configuration.

In a preferred embodiment of the present method, aromatic ethers ofvarious cinchona alkaloids are used as ligands. The term "aromaticethers" includes aryl ethers and heterocyclic ethers. A high level ofasymmetric induction can be obtained using aromatic ethers ofdihydroquinidine or dihydroquinine as ligands. For example, aromaticethers having the following formula are particularly useful: ##STR71##wherein R is phenyl, naphthyl, or o-methoxyphenyl. The stoichiometricasymmetric dihydroxylation of various dialkyl substituted olefins wasperformed using the phenyl ether derivative of dihydroquinidine. Theresults are shown in Table 6.

                                      TABLE 6                                     __________________________________________________________________________    Stoichiometric Asymmetric Dihydroxylation                                     Phenyl Ether Dihydroquinidine                                                  ##STR72##                                                                                              Reaction temp                                                                             % ee.sup.a with 3                       Entry                                                                             Olefins               (°C.)                                                                          % ee.sup.a                                                                        (for comparison)                        __________________________________________________________________________    1 2                                                                                ##STR73##              0 -78 85 95                                                                             71                                      3 4                                                                                ##STR74##              0 -78 88 93                                                                             73                                      5 6                                                                                ##STR75##              0 -78 89 94                                                                             79                                           ##STR76##            0       90  67                                      8                                                                                  ##STR77##            0       .sup. 97.sup.c                                                                    .sup. 77.sup.c                          __________________________________________________________________________     .sup.a Enantiomeric excess was determined by GLC or HPLC analysis of the      bisMosher ester derivatives.                                                  .sup.b The reaction was worked up with NaHSO.sub.3 in H.sub.2 OTHF.           .sup.c Diastereomeric excess.                                            

The reaction was performed by adding 1 eq of olefin to a 1:1 mixture ofOsO₄ and the ligand in dry toluene (0.1M) followed by a reductivework-up using lithium aluminum hydride (LiAlH₄) to yield the (R,R)-diolin 60-95% yield with good to excellent enantiomeric excess. Reactionswith α,β-unsaturated esters also proceeded with much improved enantio-and diastereoselectivities (≧90%, as shown in entries 7 and 8, Table 6)using this ligand. By lowering the reaction temperature to -78° C., thereaction with straight chain dialkyl substituted olefins proceeded withvery high enantioselectivities (≧93%, as shown in entries 2, 4 and 6 ofTable 6). In the several cases which were plotted the variance in eewith temperature closely followed the Arrhenius relationship.

Several dihydroquinidine aromatic ether derivatives were examined aschiral ligands for the asymmetric dihydroxylation of (E)-3-hexene, asshown in Table 7, below. Reactions with all of the aromatic etherderivatives tried exhibited higher enantioselectivities than thecorresponding reaction with p-chlorobenzoate dihydroquinidine. Thehighest enantioselectivity was obtained with9-O-(2'-methoxyphenyl)-dihydroquinidine (entry 2, Table 7).

                                      TABLE 7                                     __________________________________________________________________________    Stoichiometric Asymmetric Hydroxylation of (E)-3-hexene                        ##STR78##                                                                    __________________________________________________________________________    Entry                                                                             1      2       3      4         5                                              ##STR79##                                                                            ##STR80##                                                                             ##STR81##                                                                            ##STR82##                                                                               ##STR83##                                % ee                                                                              85     88      81     76        75                                        __________________________________________________________________________

In one embodiment of the present method, aromatic ether ligands wereused in the catalytic asymmetric dihydroxylation of (E)-3-hexene. Inthis embodiment, the results are summarized in Table 8. The catalyticasymmetric dihydroxylation reactions (entries 1-3, Table 8) were carriedout by slow addition of (E)-3-hexene (1 eq) to a mixture of phenyl etherdihydroquinidine (0.25 eq), N-methylmorpholine N-oxide (NMO, 1.5 eq) andOsO₄ (0.004 eq) in acetone-water (10/1, v/v) at 0° C., followed bywork-up with Na₂ S₂ O₅. The reaction proceeded faster upon addition oftetraethylammonium acetate (2 eq) to the reaction mixture (entry 4,Table 8). Potassium ferricyanide was added as the secondary oxidant(entries 5 and 6, Table 8). In these cases, slow addition of olefin wasnot required. To a mixture of (E)-3-hexane (1 eq), aromatic ether ofdihydroquinidine (0.25 eq), K₃ Fe(CN)₆ (3 eq) and potassium carbonate(K₂ CO₃ 3 eq) in tert-butyl alcohol-water (1/1, v/v) was added OsO₄(0.0125 eq); the resulting mixture was stirred at room temperature for20 hours. Reductive work-up (with Na₂ SO₃) gave the diol in 85-90% yieldwith essentially the same ee as that obtained in the stoichiometricreaction.

                                      TABLE 8                                     __________________________________________________________________________    Catalytic Asymmetric Dihydroxylation                                          of (E)-3-hexene                                                                             Secondary   Reaction                                                                            Reaction                                      Entry                                                                             Ligand                                                                            OsO.sub.4                                                                           oxidant                                                                             Additive                                                                            Temp (°C.)                                                                   Time (hr)                                                                           % ee                                    __________________________________________________________________________    1   1   0.4 mol %                                                                           NMO         0     16    70                                      2   1   0.4   NMO         0     30    75                                      3   1   0.4   NMO         0     120   85                                      4   1   0.4   NMO   Et.sub.4 NOAc                                                                       0     16    82                                      5   1    1.25 K.sub.3 Fe(CN).sub.6                                                                K.sub.2 CO.sub.3                                                                    rt    20    83                                      6   2    1.25 K.sub.3 Fe(CN).sub.6                                                                K.sub.2 CO.sub.3                                                                    rt    20    89                                      __________________________________________________________________________

Enantioselectivities in the dihydroxylation of dialkyl substitutedolefins, which were previously only possible through the use ofstoichiometric reagents at low temperature, can now be obtained in thecatalytic asymmetric dihydroxylation using these aromatic ether ligandsat room temperature. Disclosed here are two ligands which areparticularly useful in the present method: the 9-O-(9'phenanthryl)ethers and the 9-O-(4'-methyl-2'-quinolyl) ethers of dihydroquinidine(1a and 1b below) and dihydroquinine (2a and 2b below). ##STR84## The Rgroup can include other benzenoid hydrocarbons. The aromatic moietiesalso can be modified by substitutions such as by lower alkyl, alkoxy orhalogen radical groups.

Additional effective heterocyclic aromatic ligands include: ##STR85##

The improvements achieved with these new ligands are best appreciatedthrough the results shown in Table 9. A particularly important advantageis that the terminal olefins (entries 1-7, Table 9), have moved into the"useful" ee-range for the first time.

                                      TABLE 9                                     __________________________________________________________________________    Ee (%).sup.a of the Diols Resulting from Catalytic                            Asymmetric Dihydroxylation.sup.b                                              class of                                                                      olefin entry                                                                            olefin.sup.c                                                                              temp, °C.                                                                   1a(PHN)                                                                            1b(MEQ)                                                                            1c(PCB)                                                                            confign.sup.d                       __________________________________________________________________________     ##STR86##                                                                     ##STR87##                                                                     ##STR88##                                                                     ##STR89##                                                                     ##STR90##                                                                    __________________________________________________________________________     Enantiomeric excess as were determined by HPLC, GC, or .sup.1 HNMR            analysis of the bisMTPA esters .sup.7 (see supplementary materials for        details of analyses). .sup.b All reactions were performed essentially as      described in Example 20 with some variations: (1) 1-1.25 mol % OsO.sub.4      or K.sub.2 OsO.sub.2 (OH); 92) 2-25 mol % ligand, (3) 0.067-0.10 M in         olefin; (4) 18-24 h reaction time. In all cases the isolated yield of the     diol was 75-95%. .sup.c All olefins are commercially available except         entries 6 and 7..sup.8 The absolute configurations of the diols were          determined by comparison of their optical rotations with literature           values.sup.9 (entries 1, 3-5, 8, 10-13), or with an authentic diol            (R)(-)-2-phenyl-1,2-propanediol (entry 6),.sup.10 or by comparison of ORD     (entry 9)..sup.11 The remaining two (entries 2,7) are tentatively assigne     by analogy from opticla rotations of closely related diols and the            retention times of the bis MTPA esters on HPLC (see supplementary materia     for details). .sup.e Reaction was carried out at room temperature.       

The data for the new ligands 1a and 1b has been compared to the resultsfor another ligand, the ρ-chlorobenzoate 1c (last column of Table 9).Note further that the highest enantioselectivities for each substratehave been highlighted by bracketing, and that this bracketing isconspicuously sparse in the column under ligand 1c. Clearly, ligands 1aand 1b also deliver a significant ee enhancement for trans-substitutedolefins, especially those lacking aromatic substitutents (entries 8 and9).

The six possible substitution patterns for olefins are: ##STR91##

Four of these classes are represented in Table 9. The present successwith the mono- and gem-disubstituted types has essentially doubled thescope of the catalytic ADH when compared to diol production when ligandsother than aromatic ether ligands are used.

Strikingly absent from Table 9 are the results for the dihydroquinineligand analogs (i.e., 2a, 2b and 2c). The quinidine and quinine analogsof these new ligands also give very good results with the same olefinclasses shown in Table 9. Like the original ρ-chlorobenzoate ligandcomparison (1c vs 2c),^(2b) the quinine ether series gives somewhatlower ee's than their dihydroquinidine counterparts (1a vs 2a and 1b vs2b). For example, vinyl cyclooctane (entry 2) gives the S-diol in 8.8%ee using 2a compared with the R-diol in 93% ee recorded in Table 9 using1a.

The detailed general procedure for the catalytic ADH is given in noteExample 20, using ligand 1a and vinyl cyclooctane as the substrate. Notethe experimental simplicity of the process. I is performed in thepresence of air and water at either ambient or ice bath temperature. Afurther advantage is that the most expensive component, the ligand, canbe easily recovered in >80% yield.

Note also that the solid and nonvolatile osmium (VI) salt, K₂ OsO₂(OH)₄, is used in place of osmium tetroxide. This innovation should beuseful in all catalytic oxidations involving OsO₄ since it avoids therisk of exposure to volatile osmium species.

Another olefin class can be asymmetrically dihydroxylated whenO-carbamoyl-,p-chlorobenzoate- or O-phenanthrolene- substitutions ofDHQD or DHQ ligands are used in the method of the present invention.This class is the cis-disubstituted type of olefin. Table 10 shows theee's and % yields for a variety of substrates when these ligands wereused. Procedures for producing these ligands and for carrying out theADH are illustrated in Examples 23 and 24.

                                      TABLE 10                                    __________________________________________________________________________    Enantiomeric Excesses (ee's) Obtained for cis-                                Olefins with Various Dihydroquinidine Ligands; ee (% yield)                    Substrate: Ligand:                                                                      ##STR92##                                                                              ##STR93##                                                                               ##STR94##                                                                                    ##STR95##                                                                             ##STR96##                __________________________________________________________________________    DMCODHQD  20 (68)  17 (71)    4 (78)        4 (66)   17 (66)                  MPCODHQD  46 (82)   0 (54)    6 (100)       6 (90)   49 (47)                  DPCODHQD  44 (85)  10 (37)    0 (100)       3 (70)   44 (75)                  PCBODHQD  35 (92)   2 (80)   19 (83)        4 (75)   24 (63)                  PHNODHQD  22 ( )    4 (78)   37 (89)        7 (75)  -23 (56)                  PhCODHQD  17 (86)  12 (69)   14 (84)        0 (89)   10                       __________________________________________________________________________                                                        (82)                  

where the ligands are ether linked substituents of DHQD designated asdimethyl carbamoyl (DMC), methyl phenyl carbamoyl (MPC),diphenylcarbamoyl (DPC), p-chlorobenzoate (PCB), phenanthryl (PHN) andphenyl carbamoyl (PhC).

The greatest ee's were obtained when O-carbamoyl-DHQD ligands wereemployed which indicates that this class of compound is an attractiveligand for asymmetric dihydroxylation of the cis-disubstituted type ofolefin. These results also demonstrate that reasonably good yields andee's can be obtained for this olefin class and that, now, five of thesix classes of olefins can successfully be asymmetricallydihydroxylated.

In general, the concentration of the chiral ligand used will range fromapproximately 0.001M or less to 2.0M. In one embodiment, exemplifiedbelow, the solution is 0.261M in alkaloid 1 (the dihydroquinidinederivative). In one embodiment of the method, carried out at roomtemperature, the concentrations of each alkaloid represented in FIG. 1is at 0.25M. In this way, the enantiomeric excess resulting under theconditions used is maximized. The amount of chiral ligand necessary forthe method of the present invention can be varied as the temperature atwhich the reaction occurs varies. For example, it is possible to reducethe amount of alkaloid (or other chiral ligand) used as the temperatureat which the reaction is carried out is changed. For example, if it iscarried out, using the dihydroquinidine derivative, at 0° C., thealkaloid concentration can be 0.15M. In another embodiment, carried outat 0° C., the alkaloid concentration was 0.0625M.

Many oxidants (i.e., essentially any source of oxygen) can be used inthe present method. For example, amine oxides (e.g., trimethyl amineoxides), tert-butyl hydroperoxide, hydrogen peroxide, and oxygen plusmetal catalysts (e.g., copper (Cu⁺ -Cu⁺⁺ /O₂), platinum (Pt/O₂),Palladium (Pd/O₂) can be used. Alternatively, NaOCl, KIO₄, KBrO₃ orKClO₃ can be used. In one embodiment of the invention,N-methylmorpholine N-oxide (NMO) is used as the oxidant. NMO isavailable commercially (e.g., Aldrich Chemicals, 97% NMO anhydrous, oras a 60% solution in water). In addition, as stated above, potassiumferricyanide can be used in lieu of the amine oxide. Potassiumferricyanide is an efficient oxidant in the present method.

Osmium will generally be provided in the method of the present inventionin the form of osmium tetroxide (OsO₄) or potassium osmate VI dihydrate,although other sources (e.g., osmium trichloride anhydrous, osmiumtrichloride hydrate) can be used. OsO₄ can be added as a solid or insolution.

The osmium catalyst used in the method of the present invention can berecycled, for re-use in subsequent reactions. This makes it possible notonly to reduce the expense of the procedure, but also to recover thetoxic osmium catalyst. For example, the osmium catalyst can be recycledas follows: Using reduction catalysts (e.g., Pd-C), the osmium VIIIspecies is reduced and adsorbed onto the reduction catalyst. Theresulting solid is filtered and resuspended. NMO (or an oxidant), thealkaloid and the substrate (olefin) are added, with the result that theosmium which is bound to the Pd/C solid is reoxidized to OsO₄ andre-enters solution and plays its usual catalytic role in formation ofthe desired diol. This procedure (represented below) can be carried outthrough several cycles, thus re-using the osmium species. The palladiumor carbon can be immobilized, for example, in a fixed bed or in acartridge. ##STR97##

In one embodiment an olefin, such as recrystallised trans-stilbene (C₆H₅ CH:CHC₆ H₅), is combined with a chiral ligand (e.g., p-chlorobenzoylhydroquinidine), acetone, water and NMO. The components can be addedsequentially or simultaneously and the order in which they are combinedcan vary. In this embodiment, after the components are combined, theresulting combination is cooled (e.g., to approximately 0° C. in thecase of trans-stilbene); cooling can be carried out using an ice-waterbath. OsO₄ is then added (e.g., by injection), in the form of a solutionof OsO₄ in an organic solvent (e.g., in toluene). After addition ofOsO₄, the resulting combination is maintained under conditionsappropriate for the dihydroxylation reaction to proceed.

In another preferred embodiment, a chiral ligand (e.g., dihydroquinidine4-chlorobenzoate), NMO, acetone, water and OsO₄ (as a 5M toluenesolution) are combined. The components can be added sequentially orsimultaneously and the order in which they are combined can vary. Inthis embodiment, after the components are combined, the resultingcombination is cooled (e.g.. to approximately 0° C.); cooling can becarried out using an ice-water bath. It is particularly preferred thatthe combination is agitated (e.g., stirred). To this well-stirredmixture, an olefin (e.g., trans-3-hexene) is added slowly (e.g., byinjection). The optimum rate of addition (i.e., giving maximum ee), willvary depending on the nature of the olefinic substrate. In the case oftrans-3-hexene, the olefin was added over a period of about 16-20 hours.After olefin addition, the mixture can be stirred for an additionalperiod of time at the low temperature (1 hour in the case oftrans-3-hexene). The slow-addition method is preferred as it results inbetter ee and faster reaction times.

In another embodiment, a compound which accelerates hydrolysis of theosmate ester intermediates (e.g., a soluble carboxylate salt, such astetraethylammonium acetate) is added to the reaction mixture. Thecompound (approximately 1-4 equiv.) can be added to the mixture ofchiral ligand, water, solvent, oxidant and osmium catalyst and olefin,or prior to the addition of olefin, if the olefin slow-addition methodis used.

The diol-producing mechanistic scheme which is thought to operate whenthe slow-addition of olefin method is used is represented in FIG. 4.According to the proposed mechanism, at least two diol-producing cyclesexist. As shown in FIG. 4, only the first cycle appears to result inhigh ee. The key intermediate is the osmium (VIII) trioxoglycolatecomplex, shown as formula 3 in FIG. 4, which has the following generalformula: ##STR98## wherein L is a chiral ligand and wherein R₁, R₂, R₃and R₄ are organic functional groups corresponding to the olefin. Forexample, R₁, R₂, R₃ and R₄ could be alkyl, aryl, alkoxy aryloxy or otherorganic functional groups compatible with the reaction process. Examplesof olefins which can be used, and their functional groups, are shown onTable 4 hereinabove.

This complex occupies the pivotal position at the junction between thetwo cycles, and determines how diol production is divided between thecycles.

Evidence in favor of the intermediacy of the osmium (VIII)trioxoglycolate complex (formula 3, FIG. 4) is provided by the findingthat the events in FIG. 4 can be replicated by performing the process ina stepwise manner under stoichiometric conditions. These experimentswere performed under anhydrous conditions in toluene. In the processshown in FIG. 4, one equivalent of the alkaloid osmium complex (shown asformula 1, FIG. 4) is allowed to react with an olefin to give theemerald green monoglycolate ester (formula 2, FIG. 4). A differentolefin is then added, followed by an equivalent of an anhydrous amineN-oxide, and rapid formation of the bisglycolate ester (formula 4, FIG.4) is observed. Upon reductive hydrolysis of the bisglycolate ester,precisely one equivalent of each diol is liberated. These experimentsindicate that a second cycle, presumably via the osmium trioxoglycolatecomplex, is as efficient as the first in producing diols from olefins.One can also use the same olefin in both steps to run this tandemaddition sequence. When this was done using 1-phenylcyclohexene as theolefin, the ee for the first step was 81 % and the ee for the secondstep was 7% in the opposite direction (i.e., in favor of the minorenantiomer in the first step). Thus, for this substrate any intrusion ofthe second cycle is particularly damaging, and under the originalcatalytic conditions 1-phenylcyclohexene only gave 8% ee (entry 3, Table5).

Reduced ee is just part of the counterproductivity of turning on thesecond cycle; reduced turnover is the other liability. The bisosmateesters (formula 4, FIG. 4) are usually slow to reoxidize and hydrolyze,and therefore tend to tie up the catalyst. For example,1-phenylcyclohexene took 7 days to reach completion under the originalconditions (the 8% ee cited above). With slow addition of the olefin,the oxidation was complete in one day and gave the diol in 95% yield and78% ee (entry 3, Table 5).

The most important prediction arising from the mechanistic scheme shownin FIG. 4 is the minimization of the second cycle if the olefin is addedslowly. Slow addition of the olefin presumably gives the osmium (VIII)trioxoglycolate intermediate sufficient time to hydrolyze so that theosmium catalyst does not get trapped into the second cycle by reactingwith olefin. To reiterate, the second cycle not only ruins the ee butalso impedes turnover, since some of the complexes involved are slow toreoxidize and/or hydrolyze. The optimum feed rate depends on the olefin;it can be determined empirically, as described herein.

The maximum ee obtainable in the catalytic process is determined by theaddition of the alkaloid osmium complex (formula 1. FIG. 4) to theolefin (i.e., the first column in Table 5). Thus, stoichiometricadditions can be used to enable one to determine the ee-ceiling whichcan be reached or approached in the catalytic process if the hydrolysisof 3 (FIG. 4) can be made to dominate the alternative reaction with asecond molecule of olefin to give 4 (FIG. 4). In the case of terminalolefins, styrene (Table 5), the trioxoglycolate esters hydrolyzerapidly, since slow addition, or the effect of the osmate esterhydrolytic additive give only a slight increase in the ee. However, mostolefins benefit greatly from any modification which speeds hydrolysis ofthe osmate ester intermediate (3, FIG. 4) (entries 2-5, Table 5), and inextreme cases neither the effect of the osmate ester-hydrolytic additivenor slow addition is sufficient alone. Diisopropyl ethylene (entry 4,Table 5) approaches its ceiling-ee only when both effects are used inconcert, with slow addition carried out in the presence of acetate. Theother entries in the Table reach their optimum ee's through slowaddition alone, but even in these cases the addition times can besubstantially shortened if a compound, such as a tetraalkyl ammoniumacetate, is present.

In many cases, temperature also affects the ee. When the ee is reducedby the second cycle, raising the temperature can often increase it. Thisoccurs in particular, when NMO is used as the secondary oxidant. Forexample, diisopropyl ethylene gave 46% ee at 0° C. and 59% ee at 25° C.(24 h slow addition time in both cases). The rate of hydrolysis of theosmium trioxoglycolate intermediate is apparently more temperaturedependent than the rate of its reaction with olefin. This temperatureeffect is easily rationalized by the expected need to dissociate thechiral ligand from the osmium complex (3) in order to ligate water andinitiate hydrolysis, but the ligand need not dissociate for addition ofolefin to occur (in fact this second cycle olefin addition step is alsolikely to be ligand-accelerated).

When K₃ Fe(CN)₆ is used as the secondary oxidant, the effect oftemperature on the ee is opposite the effect when NMO is the secondaryoxidant. That is, lowering the temperature can often increase the eewhen potassium ferricyanide is the secondary oxidant. Also, the olefinneed not be slowly added to the mixture but can, instead, be added allat once when potassium ferricyanide is the secondary oxidant. Theseeffects and conditions apparently occur because the second cycle issuppressed when this secondary oxidant is used. The reactions of thesecond cycle do not appreciably contribute to the formation of diolswhen the secondary oxidant is potassium ferricyanide.

The following is a description of how optimum conditions for aparticular olefin can be determined. To optimize the osmium-catalyzedasymmetric dihydroxylation: 1) If from the known examples there is doubtabout what the ceiling-ee is likely to be, it can be determined byperforming the stoichiometric osmylation in acetone/water at 0° C. usingone equivalent of the OsO₄ --alkaloid complex; 2) Slow addition at 0°C.: the last column in Table 3 can be used as a guide for choosing theaddition time, bearing in mind that at a given temperature each olefinhas its own "fastest" addition rate, beyond which the ee suffers as thesecond cycle turns on. When the olefin addition rate is slow enough, thereaction mixture remains yellow-orange (color of 1, FIG. 4); when therate is too fast, the solution takes on a blackish tint, indicating thatthe dark-brown-to-black bisglycolate complex (4, FIG. 4) is beinggenerated; 3) If the ceiling ee is not reached after steps 1 and 2, slowaddition plus tetraalkyl ammonium acetate (or other compound whichassists hydrolysis of the osmate ester intermediate) at 0° C. can beused; 4) slow addition plus a soluble carboxylate salt, such astetraalkyl ammonium acetate at room temperature can also be used. Forall these variations, it is preferable that the mixtures is agitated(e.g., stirred) for the entire reaction period.

The method of the present invention can be carried out over a widetemperature range and the limits of that range will be determined, forexample, by the limit of the organic solvent used. The method can becarried out, for example, in a temperature range from about 40° C. toabout -30° C. Concentrations of individual reactants (e.g., chiralligand, oxidant, etc.) can be varied as the temperature at which themethod of the present invention is carried out. The saturation point(e.g., the concentration of chiral ligand at which results aremaximized) is temperature-dependant. As explained previously, forexample, it is possible to reduce the amount of alkaloid used when themethod is carried out at lower temperatures.

The organic solvent used in the present method can be, for example,acetone, acetonitrile, THF, DME, cyclohexane, hexane, pinacolone,tert-butanol, toluene or a mixture of two or more organic solvents.These solvents are particularly suitable when NMO is the secondaryoxidant.

When potassium ferricyanide (K₃ Fe(CN₆) is the secondary oxidant, it isadvantageous to use a combination of solvents that separate into organicand aqueous phases. Although the method of the present invention can becarried out with potassium ferricyanide as the secondary oxidant usingthe organic solvents of the preceding paragraph, asymmetricdihydroxylation does occur but the ee's are less than when separableorganic and aqueous solvent phases are employed.

The yields and ee's for a variety of organic solvents, mixed with waterand a variety of substrates are shown in Tables 11-12. Table 11 showsyields and ee's for several organic solvents (with water) for a specificsubstrate. The ligand is either DHQD-p-chlorobenzoate (PCB) orDHQD-napthyl ether. Table 12 shows the ee's for a veriety of substratesfor either t-butanol or cyclohexane as the organic phase. It is apparentfrom these Tables that preferred organic phase solvents includecyclohexane, hexane, ethyl ether and t-butyl methyl ether. The preferredaqueous solvent is water.

                  TABLE 11                                                        ______________________________________                                        Solvent Study of Catalytic ADH using                                          K.sub.3 Fe(CN).sub.6                                                          Solvent          Yield (%) ee (%)                                             ______________________________________                                        a) Solvent Effects on Styrene Diol using                                      DHQD-PCB Ligand                                                               Reaction Time = 4 hours                                                        ##STR99##                                                                    Cyclohexane      83.5      80                                                 Hexane*          59.9      76                                                 Iso-octane**     7         76                                                 t-BuOH           84.7      74                                                 t-BuOMe          80        73                                                 Toluene          78        69                                                 Et.sub.2 O       58.7      68                                                 EtOAc            64.4      65                                                 THF              61.6      61                                                 Chlorobenzene    73.6      60                                                 CH.sub.3 CN      79.0      50                                                 CH.sub.2 Cl.sub.2                                                                              73.8      49                                                 DMF              24.5      23                                                 MeOH             84.1      5.5                                                ______________________________________                                        b) Solvent Effects on Hexene Diol using                                       DHQD-PCB Ligand                                                               Reaction Time = 24 hours                                                       ##STR100##                                                                   Cyclohexane      47        74                                                 Hexane*          67.4      74                                                 t-BuOH           84.5      74                                                 t-BuOMe          61.4      71                                                 Et.sub.2 O       51.1      71                                                 EtOAc            26.7      71                                                 Toluene          32.4      69                                                 CH.sub.3 CN      81.6      68                                                 CH.sub.2 Cl.sub.2                                                                              7.6       67                                                 Chlorobenzene    9.3       66                                                 THF              74.1      65                                                 ______________________________________                                        c) Solvent Effects on Decene Diol using                                       DHQD-PCB Ligand                                                               Reaction Time = 24 hours                                                       ##STR101##                                                                   t-BuOH           60.8      79                                                 Cyclohexane      3.4       74                                                 t-BuOMe          7.6       71                                                 ______________________________________                                        d) Solvent Effects on Hexene Diol using                                       DHQD Napthyl Ether Ligand                                                     Reaction Time = 24 hours                                                       ##STR102##                                                                   t-BuOH           49.6      92                                                 Cyclohexane      36.2      91                                                 t-BuOMe          75.4      89                                                 Et.sub.2 O       47.6      89                                                 EtOAc            41.2      88                                                 Toluene          24.6      87                                                 Chlorobenzene    25.0      85                                                 THF              78.6      83                                                 CH.sub.3 CN      90.2      81                                                 CH.sub.2 Cl.sub.2                                                                              trace      7                                                 ______________________________________                                        e) Solvent Effect on Decene Diol using                                        DHQD Napthyl Ether Ligand                                                     Reaction Time = 24 hours                                                       ##STR103##                                                                   t-BuOH           40.7      94                                                 ______________________________________                                         *5 ml of tBuOMe were added to dissolve all the ligand                         ** 6 ml of tBuOMe were added to dissolve all the ligand                  

                  TABLE 12                                                        ______________________________________                                        Ee' s of Various Substrates in the Catalytic                                  ADH                                                                            ##STR104##                                                                    ##STR105##                                                                   Substrate           t-BuOH   Cyclohexane                                      ______________________________________                                         ##STR106##         73       80                                                ##STR107##         99       99                                                ##STR108##         91       92                                                ##STR109##         91       91                                                ##STR110##         91       93                                                ##STR111##         79       74                                                ##STR112##         74       74                                               ______________________________________                                    

In another embodiment of the present invention, styrene was combinedwith a chiral ligand (DHQD), acetone, water and NMO and OsO₄. The plotof amine concentration vs second-order-rate-constant K for the catalyticcis-dihydroxylation of styrene is represented in FIG. 2. The kineticdata of FIG. 2 clearly shows the dramatic effect of ligand-acceleratedcatalysis achieved by use of the method of the present invention. Pointa in FIG. 2 represents the rate of the catalytic process in the absenceof amine ligands (t1/2=108 minutes). Line b shows the rates of theprocess in the presence of varying amounts of quinuclidine, a ligandwhich substantially retards catalysis (at greater than 0.1Mquinuclidine, t1/2 is greater than 30 hours). Because of the observedretarding effect of quinuclidine (ligand-decelerated catalysis) theresult represented by line C was unexpected. That is, when the processoccurs in the presence of dihydroquinidine benzoate derivative 1 (seeFIG. 1), the alkaloid moiety strongly accelerates the catalytic processat all concentrations (with ligand 1=0.4M, t1/2=4.5 minutes), despitethe presence of the quinuclidine moiety in its structure.

The rate of the stoichiometric reaction of styrene with osmium tetroxideand that of the corresponding catalytic process were compared. Thecomparison indicates that both have identical rate constants [K_(stoic)=(5.1±0.1)×10² M⁻¹ min⁻¹ and K_(cat) =(4.9±0.4)×10² M⁻¹ min⁻¹ ], andthat they undergo the same rate acceleration upon addition of ligand 1.Hydrolysis and reoxidation of the reduced osmium species, steps whichaccomplish catalyst turnover, are not kinetically significant in thecatalytic process with styrene. It may be concluded that the limitingstep is the same in both processes and consists of the initial additionreaction forming the osmate ester (2, FIG. 1). A detailed mechanisticstudy reveals that the observed rate acceleration by added ligand 1 isdue to formation of an osmium tetroxide-alkaloid complex which, in thecase of styrene, is 23 times more reactive than free osmium tetroxide.The rate reaches a maximal and constant value beyond an (approximate)0.25M concentration of ligand 1. The onset of this rate saturationcorresponds to a pre-equilibrium between DHQD and osmium tetroxide witha rather weak binding constant (K_(eq) =18±2M⁻¹). Increasing theconcentration of DHQD above 0.25M does not result in correspondingincreases in the enantiomeric excess of the product diol. In fact, dueto the ligand-acceleration effect, the ee of the process approaches itsmaximum value much faster than the maximum rate is reached, which meansthat optimum ee can be achieved at rather low alkaloid concentrations.

At least in the case of styrene, the rate acceleration in the presenceof the alkaloid is accounted for by facilitation of the initialosmylation step. The strikingly opposite effects of quinuclidine andDHQD on the catalysis can be related to the fact that althoughquinuclidine also accelerates the addition of osmium tetroxide toolefins, it binds too strongly to the resulting osmium(VI) esterintermediate and inhibits catalyst turnover by retarding thehydrolysis/reoxidation steps of the cycle. In contrast the alkaloidappears to achieve a balancing act which renders it near perfect for itsrole as an accelerator of the dihydroxylation catalysis. It bindsstrongly enough to accelerate addition to olefins, but not so tightlythat it interferes (as does quinuclidine) with subsequent stages of thecatalytic cycle. Chelating tertiary amines [e.g., 2,2'-bipyridine and(-)-(R,R)-N,N,N',N'-tetramethyl-1,2-cyclohexanediamine) at 0.2Mcompletely inhibit the catalysis. Pyridine at 0.2M has the same effect.

As represented in Table 4, the method of the present invention has beenapplied to a variety of olefins. In each case, the face selection ruledescribed above has been shown to apply (with reference to theorientation of the olefin as represented in FIG. 1). That is, in thecase of the asymmetric dihydroxylation reaction in which thedihydroquinidine derivative is the chiral ligand, attack occurs on there- or re,re- face) and in the case in which the dihydroquininederivative is the chiral ligand, attack occurs on the si- or si,si-face. Thus, as demonstrated by the data presented in the Table 2, themethod of the present invention is effective in bringing about catalyticasymmetric dihydroxylation; in all cases, the yield of the diol was80-95%, and with the slow-addition modification, most olefins give ee'sin the rage of 40-90%.

The present method can be used to synthesize chiral intermediates whichare important building blocks for biologically active chiral molecules,such as drugs. In one embodiment, the present method was used to producean optically pure intermediate used in synthesizing the drug diltiazem(also known as cardizem). The reaction is shown in the following scheme:##STR113##

The method of the present invention is also useful to effect asymmetricvicinal oxyamination of an olefin, and may be useful for asymmetricvicinal diamination. In the case of substitution of two nitrogen or of anitrogen and oxygen, an amino derivative is used as an amino transferagent and as an oxidant. For example, the olefin to be modified, anorganic solvent, water, a chiral ligand, an amino derivative and anosmium-containing compound are combined and the combination maintainedunder conditions appropriate for the reaction to occur. The aminoderivative can be, for example, an N-chlorocarbamate or chloroamine T.Asymmetric catalytic oxyamination of recrystallized trans stilbene,according to the method of the present invention, is represented in FIG.2.

In another embodiment, the present method was used to produceintermediates for the synthesis of homobrassinolide and24-epibrassinolide, which are known to exhibit the same biologicalactivities as brassinolide. These brassinosteroids show very potentplant-growth activity at hormonal level and access to these compounds ina large quantity can only be achieved by synthetic means. ##STR114##

In another embodiment of the present method, highly optically activediol was produced from the asymmetric dihydroxylation of ethyltrans-2-octenoate. This diol has been converted to optically pureβ-lactam structure, which are well-known for their antibioticactivities: ##STR115##

An embodiment of the present invention pertains to compositions that areuseful as chiral ligands in asymmetric dihydroxylation reactions. Thesecompositions can be envisioned as being composed of three parts.

One part of the compositions is an alkaloid or alkaloid derivative.Examples of such alkaloids are the cinchona alkaloids. Quinidine,dihydroquinidine, quinine and dihydroquinine are particularly exemplarymembers of these alkaloids.

The second part of the compositions of the present invention is anorganic group or substituent of moderate size. This organic substituentis relatively bulky and often has a molecular weight in excess of 300daltons. The atomic constituents of this organic substituent usually arecarbon, hydrogen, oxygen and nitrogen but can be any type includingphosphorus and sulfur. The organic substituent can be aromatic ornonaromatic, heterocyclic or nonheterocyclic or can contain combinationsof subsidiary organic groups. The organic substituent often occupiesspace in three dimensions rather than be linear or planar although thelatter configurations can be used. Preferred embodiments of the organicsubstituent are alkaloids or alkaloid derivatives. Again, cinchonaalkaloids such as quinidine, dihydroquinidine, quinine anddihydroquinine can be utilized. When these cinchona alkaloids are used,the composition of the present invention contains two cinchonaalkaloids. In many instances the two cinchona alkaloids are identical.In those instances of incorporation of two alkaloids or alkaloidderivatives of similar or the same configuration in the composition ofthe invention, the composition has symmetry attributes that do not occurwhen the organic substituent is not an alkaloid or alkaloid derivative.It is not essential in this embodiment of the invention for thecomposition to contain two alkaloids or alkaloid derivatives, but whentwo alkaloid moieties are present, the composition has a somewhatdifferent character than when one alkaloid moiety is present. When twoalkaloids or alkaloid derivatives are incorporated in the composition ofthe invention, either one can participate in the reaction scheme asrepresented in FIG. 1. This attribute of the composition is particularlybeneficial when the two alkaloids or alkaloid derivatives are identicalbecause they participate in the reaction scheme in the same manner, asillustrated in FIG. 1.

The third part of the compositions of the present invention is a spacergroup that resides between the alkaloid or alkaloid derivative and theorganic substituent. This spacer group links the alkaloid or alkaloidderivative and the organic substituent through covalent bonds betweenthese two constituents and the spacer group. That is, the spacer groupis covalently linked to the alkaloid or alkaloid derivative and to theorganic substituent which can be another alkaloid or alkaloidderivative. When the alkaloid or alkaloid derivative (and the organicsubstituent when it is an alkaloid or alkaloid derivative) is a cinchonaalkaloid, such as dihydroquinidine, quinidine, dihydroquinine orquinine, the covalent bond is usually an ether linkage at the 9'-oxygenof the cinchona alkaloid.

The spacer group is a planar aromatic hydrocarbon. Often, the planararomatic hydrocarbon consists of one or more aromatic ring structuresbut this attribute is not required. When ring structures form thearomatic spacer group they can be heterocyclic. Nitrogen heterocyclicsare particularly preferred. Examples of such planar aromatic spacergroups are benzene, napthalene, pyridazine, pyrimidine, pyrazine,s-triazine, phthalazine, quinazoline, quinoxaline, napthyridine,pyrido[3,2-b]-pyridine, acridine, phenazine and halogen or alkylsubstituted derivatives of these compounds. In preferred embodiments ofthe invention, pyridazine or phthalazine are the spacer groups.

Compositions of this invention, therefore, are alkaloids, such ascinchona alkaloids, or alkaloid derivatives covalently linked to planararomatic spacer groups which, in turn, are covalently linked to organicsubstituents whose molecular weight is at least 300 daltons. Theseorganic substituents often are alkaloids, such as cinchona alkaloids, oralkaloid derivatives. In many instances, the organic substituents areidentical to the alkaloids or alkaloid derivatives that are alsocovalently linked to the spacer group. In these instances, thecompositions of the present invention are two identical alkaloids, suchas cinchona alkaloids, or alkaloid derivatives covalently linked to eachother through a planar aromatic spacer group. Particularly preferredembodiments of this aspect of the present invention are phthalazine orpyridazine which are disubstituted with either dihydroquinidine,quinidine, dihydroquinine or quinine. These embodiments are1,4-bis-(9'-O-dihydroquinidyl)-phthalazine,1,4-bis-(9'-O-quinidyl)-phthalazine,3,6-bis-(9'-O-dihydroquinidyl)-pyridazine,3,6-bis-(9'-O-quinidyl)-pyridazine,1,4-bis-(9'-O-dihydroquinyl)-phthalazine,1,4-bis-(9'-O-quinyl)-phthalazine,3,6-bis-(9'-O-dihydroquinyl)-pyridazine and3,6-bis-(9'-O-quinyl)-pyridazine.

Another embodiment of the present invention pertains to methods forasymmetric dihydroxylation of olefins using the compositions justdescribed in the immediately preceding paragraphs as the chiral ligandsin the asymmetric dihydroxylation reaction. In these methods, the chiralligands that are alkaloids or alkaloid derivatives covalently linked toplanar aromatic spacer groups which, in turn, are covalently linked toorganic substituents whose molecular weight is at least 300 daltons arecalled chiral auxiliaries. A chiral auxiliary, an organic solvent, anaqueous solution, a base, a ferricyanide salt and an osmium-containingcatalyst are combined as previously described. The olefin can be presentas this combination is being formed or it can be added after the listedcombination has been made. The resulting combination is maintained, aspreviously described, under conditions that allow asymmetric addition tothe olefin to occur. The difference between the methods of the presentembodiment and previously described methods of other embodiments is thechiral ligand (here the chiral auxiliary) that is used in the asymmetricdihydroxylation reaction.

In preferred embodiments of these methods of the present invention, thealkaloids of the chiral auxiliary are cinchona alkaloids such asdihydroquinidine, quinidine, dihydroquinine and quinine. In furtherpreferred embodiments of these methods, the organic substituents arealkaloids, such as cinchona alkaloids, or alkaloid derivatives. In stillfurther preferred embodiments of these methods, the planar aromaticspacer group is a nitrogen heterocyclic such as pyridazine orphthalazine. In particularly preferred embodiments of these methods, thechiral auxiliary is a bis-(cinchona alkaloid)-pyridazine orbis-(cinchona alkaloid)-phthalazine listed above.

In these methods of the present invention, a ferricyanide salt is usedas the secondary oxidant. The important moiety of the salt is theferricyanide anion. The specific cation of the salt is not critical andcan be, for example, potassium, sodium, calcium, magnesium or an organiccation. In particular embodiments of these methods, potassiumferricyanide is the chosen salt.

These methods of the present invention, using the chiral auxiliaries,produce asymmetrically dihydroxylated olefins with better ee values thanwhen previously described chiral ligands are used. This is particularlyevident for 1,2-diols synthesized from terminal mono- and1,1-disubstituted olefins in a temperature range from 0° C. to 25° C.This feature is shown in Table 16 of Example 26.

In addition, in these methods of the present invention a small amount ofchiral auxiliary is all that is needed to produce asymmetricallydihydroxylated olefins with good yields and ee values. This is shown inTable 17 of Example 26.

EXAMPLE 1 Asymmetric Dihydroxylation of Stilbene

The following were placed sequentially in a 2 L bottle (or flask): 180.2g (1.0M) of recrystallised trans stilbene (Aldrich 96%), 62.4 g (0.134moles; 0.134 eq) of the p-chlorobenzoate of hydroquinidine (1), 450 mLof acetone, 86 mL of water (the solution is 0.261M in alkaloid 1) and187.2 g (1.6 mol, 1.6 eq.) of solid N-Methylmorpholine N-Oxide (NMO,Aldrich 97%). The bottle was capped, shaken for 30 seconds, cooled to0°-4° C. using an ice-water bath. OsO₄ (4.25 mL of a solution preparedusing 0.120 g OsO₄ /mL toluene; 0.002 Mol %; 0.002 eq.) was injected.The bottle was shaken and placed in a refrigerator at ca. 4° C. withoccasional shaking. A dark purple color developed and was slowlyreplaced by a deep orange one; the heterogeneous reaction mixturegradually became homogeneous and at the end of the reaction, a clearorange solution was obtained. The reaction can be conveniently monitoredby TLC (silica gel; CH₂ Cl₂ ; disappearance of the starting material ata defined Rf). After 17 hours, 100 g of solid sodium metabisulfite (Na₂S₂ O₅) were added, the reaction mixture was shaken (1 minute) and leftat 20° C. during 15 minutes. The reaction mixture was then diluted by anequal volume of CH₂ Cl₂ and anhydrous Na₂ SO₄ added (100 g). Afteranother 15 minutes, the solids were removed by filtration through a padof celite, washed three times with 250 mL portions of CH₂ Cl₂ and thesolvent was evaporated under vacuum (rotatory-evaporator, bathtemperature=30°-35° C.).

The crude oil was dissolved in ethyl acetate (750 mL), extracted threetimes with 500 ml. portions of 2.0M HCl, once with 2.0M NaOH, dried overNa₂ SO₄ and concentrated in vacuo to leave 190 g (89%) of the crude diolas a pale yellow solid. The enantiomeric excess of the crude R,R-diolwas determined to be 78% by HPLC analysis of the derived bis-acetate(Pirkle 1A column using 5% isopropanol/hexane mixture as eluant.Retention times are: t1=18.9 minutes; t2=19.7 minutes. Recrystallizationfrom about 1000 ml. CH₂ Cl₂ gave 150 g (70%) of pure diol (ee=90%). Asecond recrystallization gave 115 g of diol (55% yield) of 99% ee. Ee(enantiomeric excess) is calculated from the relationship (for the Renantiomer, for example): percent

    e.e.=[(R)-(S)/[(R)+(S)]×100.

The aqueous layer was cooled to 0° C. and treated with 2.0M NaOH (about500 mL) until pH=7. Methylene chloride was added (500 mL) and the pHadjusted to 10-11 using more 2.0M NaOH (about 500 mL). The aqueous layerwas separated, extracted twice with methylene chloride (2×300 mL) andthe combined organic layers were dried over Na₂ SO₄. The solvent wasremoved in vacuo to provide the alkaloid as a yellow foam. The crudealkaloid was dissolved in ether (1000 mL), cooled to 0° C. (ice-bath)and treated with dry HCl until acidic pH (about 1-2). The faint yellowprecipitate of p-chlorobenzoylhydroquinidine hydrochloride was collectedby filtration and dried under high vacuum (0.01 mm Hg).

The free base was liberated by suspending the salt in ethyl acetate (500mL), cooling to 0° C. and adding 28% NH₄ OH until pH=11 was reached.After separation, the aqueous layer was extracted twice with ethylacetate, the combined organic layers were dried over Na₂ SO₄ and thesolvent removed in vacuo to give the free base as a white foam.

EXAMPLE 2 Asymmetric Dihydroxylation of Stilbene

To a 3 L, 3-necked round-bottomed flask equipped with a mechanicalstirrer and two glass stoppers at room temperature were addedE-1,2-diphenylethene (Trans-stilbene) (180.25 g, 1.0 mol, 1.0 eq),4-methylmorpholine N-oxide (260 mL of a 60% by wt. aqueous solution (1.5mol, 1.5 eq) dihydroquinidine 4-chlorobenzoate (23.25 g, 0.05 mol, 0.05eq) 375 mL acetone and 7.5 mL H₂ O. The solution was 0.1M in alkaloid Min olefin, and the solvent was 25% water/75% acetone (v/v). The flaskwas immersed in a 0° C. cooling bath and stirred for 1 h. Osmiumtetroxide (1.0 g, 4.0 mmol., 4.0×10⁻³ eq) was added in one portionproducing a milky brown-yellow suspension. The reaction mixture was thenstirred at 0° C. for 24 h and monitored by silica TLC (3:1 CH₂ Cl₂ :Et₂O v/v). At this point, sodium metabisulfite (285 g, 1.5 mol) was added,the mixture was diluted with 500 mL of CH₂ Cl₂, warmed to roomtemperature, and stirred at room temperature for 1 h. Anhydrous sodiumsulfate (50 g) was added and the mixture was stirred at room temperatureovernight. The suspension was filtered through a 20 cm Buchner funnel,the filtrand was rinsed thoroughly with acetone (3×250 mL), and thefiltrate was concentrated to a brown paste on a rotary evaporator withslight heating (bath temperature 30°-40° C). The paste was dissolved in3.5 L of EtOAc, transferred to a 6 L separatory funnel and washedsequentially with H₂ O (2×500 mL), and brine (1×500 mL). The initialaqueous washes were kept separate from the subsequent acid washes whichwere retained for alkaloid recovery. The organic layer was dried (Na₂SO₄), and concentrated to give the crude diol in quantitative yield(222.7 g, 1.04 mol, 104%). The ee of the crude product was determined by¹ H NMR analysis of the derived bis-Mosher ester to be 90%. Onerecrystallization from hot 95% acueous ethanol (3 mL/g) afforded 172-180g (80-84%) of enantiomerically pure stilbene diol as a white solid, mp145.5°-146.5° C., [α]_(D) ²⁵ =91.1° (c=1.209, abs EtOH).

EXAMPLE 3 Asymmetric Dihydroxylation of Stilbene

Asymmetric dihydroxylation of stilbene was carried out as described inExample 1, except that 1.2 equivalents of NMO were used.

EXAMPLE 4 Asymmetric Dihydroxylation of Stilbene

Asymmetric dihydroxylation of stilbene was carried out as described inExample 1, except that 1.2 equivalents of NMO, as a 62% wt. solution inwater, were used.

EXAMPLE 5 Preparation of dihydroquinidine derivative

Preparation of dihydroquinidine by catalytic reduction of quinidine

To a solution of 16.2 g of quinidine (0.05 mol) in 150 mL of 10% H₂ SO₄(15 g conc H₂ SO₄ in 150 mL H₂ O) was added 0.2 g of PdCl₂ (0.022 eq;0.0011 mol). The reaction mixture was hydrogenated in a Parr shaker at50 psi pressure. After 2 h, the catalyst was removed by filtrationthrough a pad of celite and washed with 150 mL of water. The faintyellow solution so obtained was slowly added to a stirred aqueous NaOHsolution (15 g of NaOH in 150 mL H₂ O. A white precipitate immediatelyformed and the pH of the solution was brought to 10-11 by addition ofexcess aqueous 15% NaOH. The precipitate was collected by filtration,pressed dry and suspended in ethanol (175 mL). The boiling solution wasquickly filtered and upon cooling to room temperature, white needlescrystallized out. The crystals were collected and dried under vacuum(90° C.; 0.05 mm Hg) overnight. This gave 8.6 g (52.7%) of puredihydroquinidine mp=169.5°-170° C. The mother liquor was placed in afreezer at -15° C. overnight. After filtration and drying of thecrystals, another 4.2 g (21.4%) of pure material was obtained, raisingthe total amount of dihydroquinidine to 12.8 g (74.1%).

Preparation of dihydroquinidine p-chlorobenzoate (ligand 1)

From dihydroquinidine hydrochloride (Aldrich)

To cooled (0° C.) suspension of 100 g dihydroquinidine hydrochloride(0.275 mol) in 300 mL of dry CH₂ Cl₂ was added, over 30 minutes withefficient stirring, 115 mL of Et₃ N (0.826 eq; 3 eqs) dissolved in 50 mLof CH₂ Cl₂. The dropping funnel was rinsed with an additional 20 mL ofCH₂ Cl₂. After stirring 30 minutes at 0° C., 42 mL of p-chlorobenzoylchloride (0.33 mol;57.8 g; 1.2 eq) dissolved in 120 mL of CH₂ Cl₂ wasadded dropwise over a period of 2 h. The heterogeneous reaction mixturewas then stirred 30 minutes at 0° C. and 1 hour at room temperature; 700mL of a 3.0M NaOH solution was then slowly added until pH=10-11 wasobtained. After partitioning, the aqueous layer was extracted with three100 mL portions of CH₂ Cl₂. The combined organic layers were dried overNa₂ SO₄ and the solvent removed in vacuo (rotatory evaporator). Thecrude oil was dissolved in 1 L of ether, cooled to 0° C. and treatedwith HCl gas until the ether solution gives a pH of about 2 using wet pHpaper. The slightly yellow precipitate was collected and dried undervacuum to give 126 g (91.5%) of dihydroquinidine p-chlorobenzoatehydrochloride.

The salt was suspended in 500 mL of ethyl acetate, cooled to 0° C. andtreated with 28% NH₄ OH until pH=11 was reached. After separation, theaqueous layer was extracted with two 200 mL portions of ethyl acetate.The combined organic layers were dried over Na₂ SO₄ and the solventremoved under vacuum, leaving the free base 1 as a white foam (112 g;88% overall). This material can be used without further purification, orit can be recrystallized from a minimum volume of hot acetonitrile togive an approximately 70-80% recovery of colorless crystals: mp:102°-104° C., []²⁵ D-76.5° [c1.11, EtOH); IR (CH₂ Cl₂) 2940, 2860, 1720,1620, 1595, 1520, 1115, 1105, 1095, 1020 cm⁻¹ ; ¹ H NMR (CDCl₃) 8.72 (d,1H, J=5Hz), 8.05 (br d, 3H, J=9.7Hz), 7.4 (m, 5H), 6.72 (d, 1H,J=7.2Hz), 3.97 (s, 3H), 3.42 (dd, 1H, J=9, 19.5Hz), 2.9-2.7 (m, 4H),1.87 (m, 1H), 1.75 (br s, 1H), 1.6-1.45 (m, 6H), 0.92 (t, 3H, J=7Hz).Anal. Calcd for C₂₇ H₂₉ ClN₂ O₃ : C, 69.74; H, 6.28; Cl, 7.62; N, 6.02.Found: C, 69.95;H, 6.23; Cl, 7.81; N, 5.95.

From dihydroquinidine

To a 0° C. solution of 1.22 g dihydroquinidine (0.0037 mol) in 30 mL ofCH₂ Cl₂ was added 0.78 mL of Et₃ N (0.0056 mol; 1.5 eq), followed by0.71 mL of p-chlorobenzoyl chloride (0.005 mol; 1.2 eq) in 1 mL CH₂ Cl₂.After stirring 30 minutes at 0° C. and 1 hour at room temperature, thereaction was quenched by the addition of 10% Na₂ CO₃ (20 mL). Afterseparation, the aqueous layer was extracted with three 10 mL portions ofCH₂ Cl₂. The combined organic layers were dried over Na₂ SO₄ and thesolvent removed under vacuum. The crude product was purified asdescribed above. Dihydroquinidine p-chlorobenzoate (1) was obtained in91% yield (1.5 g) as a white foam.

Recovery of dihydroquinidine p-chlorobenzoate

The aqueous acidic extracts (see EXAMPLE 1) were combined, cooled to 0°C. and treated with 2.0M NaOH solution (500 mL) until pH=7 was obtained.Methylene chloride was added (500 mL) and the pH was adjusted to 10-11using more 2.0M NaOH. The aqueous layer was separated and extracted withtwo 300 mL portions of CH₂ Cl₂. The combined organic layers were driedover Na₂ SO₄ and concentrated to leave the crude alkaloid as a yellowfoam. The crude dihydroquinidine p-chlorobenzoate (1) was dissolved in 1L of ether, cooled to 0° C. and HCl gas was bubbled into the solutionuntil a pH of 1-2 was obtained using wet pH paper. The pale yellowprecipitate of 1 as the hydrochloride salt was collected by filtrationand dried under high vacuum (0.01 mm Hg). The free base was liberated bysuspending the salt in 500 mL of ethyl acetate, cooling theheterogeneous mixture to 0° C. and adding 28% NH₄ OH (or 15% NaOH) untilpH=11 was obtained. After separation, the aqueous layer was extractedwith two 100 mL portions of ethyl acetate, the combined organic layerswere dried over Na₂ SO₄ and the solvent removed in vacuo to give 56 g(91% recovery) of pure dihydroquinidine p-chlorobenzoate (1) as a whitefoam.

EXAMPLE 6 Preparation of dihydroquinine derivative

Preparation of dihydroquinine p-chlorobenzoate

The catalytic hydrogenation and p-chlorobenzoylation were conducted asdescribed for the dihydroquinidine p-chlorobenzoate to give a whiteamorphous solid in 85-90% yield. This solid can be used without furtherpurification, or it can be recrystallized from a minimum volume of hotacetonitrile to afford colorless crystals: Mp:130°-133° C., [α]²⁵ D+150°(c 1.0, EtOH). The physical properties of the solid beforerecrystallization (i.e., the "white amorphous solid") are as follows:[]²⁵ D+142.1 (C=1, EtOH); IR (CH₂ Cl₂) 2940, 2860, 1720, 1620, 1595,1508, 1115, 1105, 1095, 1020 cm⁻¹, ¹ H NMR (CDCl₃)d 8.72 (d, 1H, J=5Hz),8.05 (br d, 3H, J=8Hz), 7.4 (m, 5H), 6.7 (d, 1H, J=8Hz), 4.0 (s, 3H),3.48 (dd, 1H, J=8.5, 15.8Hz), 3.19 (m, 1H), 3.08 (dd, 1H, J=11, 15Hz),2.69 (ddd, 1H, J=5, 12, 15.8Hz), 2.4 (dt, 1H, J=2.4, 15.8Hz), 1.85-1.3(m, 8H), 0.87 (t, 3H, J=Hz). Anal. Calcd for C₂₇ H₂₉ ClN₂ O₃ : C, 69.74;H, 6.28; Cl, 7.62; N, 6.02. Found: C, 69.85; H, 6.42; Cl, 7.82 ; N,5.98.

Recovery of dihydroquinine p-chlorobenzoate (2)

The procedure is identical to that described above for recovery of 1.

EXAMPLE 7 Procedure for Asymmetric Dihydroxylation of Trans-3-hexeneUnder "Slow Addition" Conditions

To a well stirred mixture of 0.465 g (1 mmol, 0.25 eq=0.25M in L)dihydroquinidine 4-chlorobenzoate (Aldrich, 98%), 0.7 g (6 mmol, 1.5 eq)N-methylmorpholine N-oxide (Aldrich, 97%), and 32 L of a 0.5M toluenesolution of osmium tetroxide (16 mol, 4×10⁻³ equiv), in 4 mL of anacetone-water mixture (10:1 v/v) at 0° C., neat 0.5 mL (0.34 g, 4 mmol)trans-3-hexene (Wiley, 99.9%) was added slowly, via a gas tight syringecontrolled by a syringe pump and with the tip of the syringe needleimmersed in the reaction mixture, over a period of 16 h. The mixturegradually changed from heterogeneous to homogeneous. After the additionwas complete, the resulting clear orange solution was stirred at 0° C.for an additional hour. Solid sodium metabisulfite (Na₂ S₂ O₅, 1.2 g)was added and the mixture was stirred for 5 min, and then diluted withdichloromethane (8 mL) and dried (Na₂ SO₄). The solids were removed byfiltration, and washed three times with dichloromethane. The combinedfiltrates were concentrated, and the residual oil was subjected to flashcolumn chromatography on silica gel (25 g, elution with diethylether-dichloromethane, 2:3 v/v, R_(f) 0.33) and collection of theappropriate fractions afforded 0.30-0.32 g (85-92% yield) of thehexanediol. The enantiomeric excess of the diol was determined by GLCanalysis (5% phenyl-methylsilicone, 0.25 m film, 0317 mm diameter, 29 mlong) of the derived bis-Mosher ester to be 70%.

When the above reaction was repeated with 1.2 mL (6 mmol, 1.5 eq) 60%aqueous NMO (Aldrich) in 4 mL acetone, an ee of 71% was obtained. Thus,this aqueous NMO gives equivalent results and is almost twenty timesless expensive than the 97% solid grade. With an alkaloid concentrationof only 0.1M (i.e., 0.186 g) and with an olefin addition period of 20hours at 0° C., the ee was 65%. A small sacrifice in ee thus leads to alarge saving in alkaloid. At 0° C., both trans-3-hexene and trans--methylstyrene reach their maximum ee value between 0.20 and 0.25Malkaloid concentration.

EXAMPLE 8 Asymmetric Dihydroxylation of 1-Phenylcyclohexene with Et₄NOAc-4H₂ O

The procedure set out in Example 1 was followed, except that1-phenylcyclohexene (1.0M) was substituted for trans-stilbene. Thereaction was allowed to proceed for three days, after which only 40%conversion to the diol was obtained (8% ee).

The above procedure was repeated, with the difference that 2 equivalentsof tetraethyl ammonium acetate (Et₄ NOAc-4H₂ O) was added to thereaction mixture at the beginning of the reaction. Fifty-two (52%)percent ee was obtained using this procedure, and the reaction wasfinished in about one day.

EXAMPLE 9 Asymmetric Dihydroxylation of trans-Stilbene under"phase-transfer" conditions in toluene

To a well-stirred mixture of 58.2 mg (0.125 mmol; 0.25 eq.) of thep-chlorobenzoate of hydroquinidine, 1 mL of toluene, 88 mg (0.75 mmol;1.5 eq.) of N-methylmorpholine N-oxide, 181 mg (1 mmol; 2 eq.) oftetramethylammonium hydroxide pentahydrate, 57 μL (2 mmol; 2 eq.) ofacetic acid, 0.1 mL of water, and OsO₄ (4.2 μL of solution preparedusing 121 mg OsO₄ /mL toluene; 0.004 Mol %, 0.004 eq.) at roomtemperature, a toluene solution (1 mL) of 90 mg (0.4 mmol) oftrans-stilbene was added slowly, with a gas-tight syringe controlled bya syringe pump and with the tip of the syringe needle immersed in thereaction mixture, over a period of 24 h. After the addition wascompleted, 10% NaHSO₃ solution (2.5 mL) was added to the mixture, andthe resulting mixture was stirred for 1 h. Organic materials wereextracted with ethyl acetate, and the combined extracts were washed withbrine and dried over Na₂ SO₄. The solvent was evaporated under reducedpressure, and the residual oil was subjected to column chromatography onsilica gel (5 g, elution with hexane-ethyl acetate, 2:1 v/v, R_(f) 0.17)to afford 67.3 mg (63%) of the diol. The enantiomeric excess of the diolwas determined by HPLC analysis of the derived bis-acetate (Pirkle 1Acolumn using 5% isopropanol/hexane mixture as eluant. Retention timesare: t₁ =22.6 minutes; t₂ =23.4 minutes) to be 94%.

EXAMPLE 10 Asymmetric Dihydroxylation of trans-Methyl 4-methoxycinnamateunder phase-transfer conditions in toluene

To a well-stirred mixture of 116.3 mg (0.25 eq.) of the p-chlorobenzoateof hydroquinidine, 2 mL of toluene, 175.8 mg (1.5 mmol; 1.5 eq.) ofN-methylmorpholine N-oxide, 522 mg (2 mmol; 2 eq.) of tetraethylammoniumacetate tetrahydrate, 0.2 mL of water, and OsO₄ (8.4 μL of solutionprepared using 121 mg OsO₄ /mL toluene; 0.004 Mol %, 0.004 eq.) at roomtemperature, a toluene solution (1 mL) of 192 mg (1 mmol) oftrans-methyl 4-methoxycinnamate was added slowly, with a gas-tightsyringe controlled by a syringe pump and with the tip of the syringeneedle immersed in the reaction mixture, over a period of 24 h. Afterthe addition was complete, 10% NaHSO₃ solution (5 mL) was added to themixture, and the resulting mixture was stirred for 1 h. Organicmaterials were extracted with ethyl acetate, and the combined extractswere washed with brine and dried over Na.sub. 2 SO₄. The solvent wasevaporated under reduced pressure, and the residual oil was subjected tocolumn chromatography on silica gel (10 g, elution with hexane-ethylacetate, 2:1 v/v R_(f) 0.09) to afford 118.8 mg (53%) of the diol. Theenantiomeric excess of the diol was determined by HPLC analysis of thederived bis-acetate (Pirkle Covalent Phenyl Glycine column using 10%isopropanol/hexane mixture as eluant. Retention times are: t₁ =25.9minutes; t₂ =26.7 minutes) to be 84%.

EXAMPLE 11 Asymmetric Dihydroxylation of trans-Stilbene in the presenceof Boric Acid

To a well-stirred mixture of 58.2 mg (0.125 mmol; 0.25 eq) of thep-chlorobenzoate of hydroquinidine, 70 mg (0.6 mmol; 1.2 eq.) ofN-methylmorpholine N-oxide, 37 mg (0.6 mmol; 1.2 eq.) of boric acid, 0.5mL of dichloromethane, and OsO₄ (4.2 μL of a solution prepared using 121mg OsO₄ /mL toluene; 0.004 Mol %, 0.004 eq.) at room temperature, adichloromethane solution (1 mL) of 90 mg (0.5 mmol) of trans-stilbenewas added slowly, with a gas-tight syringe controlled by a syringe pumpand with the tip of the syringe needle immersed in the reaction mixture,over a period of 24 h. After the addition was complete, 10% NaHSO₃solution (2.5 mL) was added to the mixture, and the resulting mixturewas stirred for 1 h. Organic materials were extracted with ethylacetate, and the combined extracts were washed with brine and dried overNa₂ SO₄. The solvent was evaporated under reduced pressure, and theresidual oil was subjected to column chromatography on silica gel (5 g,elution with hexane-ethyl acetate, 2:1 v/v, R_(f) 0.17) to afford 78.3mg (73%) of the diol. The enantiomeric excess of the diol was determinedby ¹ H-NMR (solvent: CDCl₃) analysis of the derived bis-Mosher ester tobe 94%.

EXAMPLE 12 Asymmetric Dihydroxylation of trans-Methyl 4-methoxycinnamatein the presence of Boric Acid

To a well-stirred mixture of 116.3 mg (0.25 mmol; 0.25 eq.) of thep-chlorobenzoate of hydroquinidine, 175.8 mg (1.5 mmol; 1.5 eq.) ofN-methylmorpholine N-oxide, 74.4 mg (1.2 mmol; 1.2 eq.) of boric acid, 1mL of dichloromethane, and OsO₄ (8.4 μL of a solution prepared using 121mg OsO₄ /mL toluene, 0.004 mol %, 0.004 eq.) at room temperature, adichloromethane solution (1 mL) of 192 mg (1 mmol) of trans-methyl4-methoxycinnamate was added slowly, with a gas-tight syringe controlledby a syringe pump and with the tip of the syringe needle immersed in thereaction mixture, over a period of 24 h. After the addition wascomplete, 10% NaHSO₃ solution (5 mL) was added to the mixture, and theresulting mixture was stirred for 1 h. Organic materials were extractedwith ethyl acetate, and the combined extracts were washed with brine anddried over Na₂ SO.sub. 4. The solvent was evaporated under reducedpressure, and the residual oil was subjected to column chromatography onsilica gel (10 g, elution with hexane-ethyl acetate, 2:1 v/v, R_(f)0.09) to afford 151.1 mg (67%) of the diol. The enantiomeric excess ofthe diol was determined by HPLC analysis of the derived bis-acetate(Pirkle Covalent Phenyl Glycine column using 10% isopropanol/hexanemixture as eluant. Retention times are: t₁ =24.0 minutes; t₂ =24.7minutes) to be 76%.

EXAMPLE 13 Asymmetric Dihydroxylation of trans-β-Methylstyrene in thepresence of Boric Acid

To a well-stirred mixture of 58.2 mg (0.125 mmol; 0.25 eq) of thep-chlorobenzoate of hydroquinidine, 70 mg (0.6 mmol; 1.2 eq) ofN-methylmorpholine N-oxide, 72 mg (0.6 mmol; 1.2 eq) of phenylboricacid, 0.5 mL of dichloromethane, and OsO₄ (4.2 μL [of a solutionprepared using 121 mg OsO₄ /mL toluene; 0.004 Mol %, 0.004 eq) at 0° C.,a dichloromethane solution] (0.5 mL), 65 μL (0.5 mmol)trans-β-methylstyrene was added slowly, with a gas-tight syringecontrolled by a syringe pump and with the tip of the syringe needleimmersed in the reaction mixture, over a period of 24 h. After theaddition was complete, 10% NaHSO₃ solution (2.5 mL) was added to themixture, and the resulting mixture was stirred for 1 h. Organicmaterials were extracted with ethyl acetate, and the combined extractswere washed with brine and dried over Na₂ SO₄. The solvent wasevaporated under reduced pressure, and the residual oil was subjected tocolumn chromatography on silica gel (5 g, elution with hexane-ethylacetate, 2:1 v/v, R_(f) 0.62) to afford 109 mg (91%) of thephenylborate. The phenylborate was dissolved into acetone (3 mL) and1,3-propandiol (0.5 mL), and the resulting mixture was stood for 2 h atroom temperature. The solvent was evaported under reduced pressure, andthe residual oil was subjected to column chromatography on silica gel (5g, elution with hexaneethyl acetate, 2:1 v/v, R_(f) 0.10) to afford 48.6mg (70%) of the diol. The enantiomeric excess of the diol was determinedby HPLC analysis of the derived bis-acetate (Pirkle 1A column using 0.5%isopropanol/hexane mixture as eluant. Retention times are: t₁ =17.1minutes; t₂ =18.1 minutes) to be 73%.

EXAMPLE 14 General Method for the Asymmetric Dihydroxylation oftrans-Stilbene Using A Polymeric Alkaloid Ligand

To a magnetically stirred suspension of the alkaloid copolymer (such aspolymers 2-4, Table 1; 0.25 eq based on alkaloid incorporated), NMO (1.5eq), and tetraethylammonium acetate tetrahydrate (1.0 eq) inacetone-water (10/1 , v/v) a solution of OsO₄ (0.01 eq) in eithertoluene or acetonitrile was added. After stirring for 10-30 minutes,trans-stilbene (1.0 eq) was added and the reaction mixture was stirredfor the given time and monitored by silica gel TLC (hexane-EtOAc 2/1,v/v). The concentration of olefin in the reaction mixture was 0.3-0.4M.After the reaction was complete, the mixture was diluted with acetone,water, hexane or ether and centrifuged or filtered to separate thepolymer from the reaction mixture. The supernatant was then worked up asdescribed by Jacobsen et al., J. Am. Chem. Soc., 110:1968 (1988).

EXAMPLE 15 Asymmetric Dihydroxylation of trans-Stilbene Using APolymer-Bound Alkaloid Ligand and Potassium Ferricyanide

To a well-stirred mixture of the alkaloid polymer (0.05 mmol, based onalkaloid incorporated), potassium ferricyanide (0.198 g, 0.6 mmol) andpotassium carbonate (0.83 g, 0.6 mmol) in tert-butanol (1.5 mL) andwater (1.5 mL), was added OsO₄ solution (0.0025 mmol) in acetonitrile.After stirring for 10 min, trans-stilbene (36 mg, 0.2 mmol) was addedand the mixture was stirred for the given time and monitored by silicagel TLC. When the reaction was complete, water (3.0 mL) was added andthe mixture was filtered. The filtrate was extracted withdichloromethane (5 mL×2). the organic layer was stirred for 1 h withexcess sodium metabisulfite and sodium sulfate. This suspension wasfiltered and the filtrate was concentrated to provide crude diol, whichwas purified on a silica gel column.

EXAMPLE 16 Asymmetric Dihydroxylation of Olefins in the Presence ofPotassium Ferricyanide

The general procedure for asymmetric dihydroxylation of olefins usingpotassium ferricyanide:

To a well-stirred mixture of 0.465 g (1 mmol, 0.5 equiv=0.033M inligand) dihydroquinidine p-cholorobenzoate (Aldrich, 98%), 1.980 g (6mmol, 3.0 equiv) potassium ferricyanide, 0.830 g (6 mmol, 3.0 equiv)potassium carbonate, and 0.5 mL of a 0.05M tert-butyl alcohol solutionof osmium tetroxide (0.025 mmol, 0.0125 equiv) in 30 mL of a tert-butylalcohol-water mixture (1:1, v/v) at room temperature, olefin (2 mmol)was added at at once. The reaction mixture was stirred for 24 h at roomtemperature. Solid sodium sulfite (Na₂ SO₃, 1.5 g) was added, and themixture was stirred for an additional hour. The solution obtained wasconcentrated to dryness under reduced pressure, and the residue wasextracted with three portions of ether. The combined extracts were dried(Na₂ SO₄) and evaporated. The residue was purified by columnchromatography (silica gel, dichloromethane-ether).

EXAMPLE 17 Preparation of 9-O-Phenyldihydroquinidine

To a suspension of dihydroquinidine (4.0 g) in THF (40 mL) was addedη-BuLi (2.5M solution in hexane, 4.95 mL) at 0° C. The ice bath wasremoved and the reaction mixture stood at room temperature for 10minutes. To the resulting yellow solution, solid cuprous chloride (1.2g) was added. After stirring for 30 minutes, pyridine (30 mL) and HMPA(1 mL) were added. After stirring for 5 minutes, phenyl iodide (1.37 mL)was added and the mixture was stirred at reflux for 36 h. To theresulting mixture, aqNH₄ OH was added and the mixture was extracted withethyl ether. The extract was dried over MgSO₄. The solvent wasevaporated under reduced pressure, and the residue was subjected tocolumn chromatography on silica gel (100 g, elution with ethylacetate-ethanol, 9:1 v/v, Rf 0.23) to afford 1.77 g(y. 36%) of9-O-phenyldihydroquinidine.

¹ H NMR (CDCl₃)δ8/68 (1H, d, J=4.5 Hz), 8.08 (1H, d, J =9 Hz), 7.3-7.5(3H, m), 7.17 (2H, t, J=8 Hz), 6.89 (1H, t, J=8 Hz), 6.78 (2H, d, J=8Hz), 6.02 (1H, d, J =3 Hz), 4.00 (3H, s), 2.7-3.3 (5H, m), 2.2-2.4 (1H,m), 1.4-1.9 (6H, m), 1.1-1.3 (1H, m), 0.97 (3H, t, J=7 Hz).

EXAMPLE 18 Asymmetric Dihydroxylation of Trans-3-Hexene Using9-O-Phenyldihydroquinidine and Potassium Ferricyanide

To a well-stirred mixture of 46 mg of 9-O-phenyldihydroquinidine, 396 mgof potassium ferricyanide, 166 mg of potassium cabonate and 8 μL of a0.63M toluene solution of osmium tetroxide in 6 mL of t-butylalcohol-water (1:1, v/v) at room temperature was added 50 μL oftrans-3-hexene all at once. The reaction mixture was stirred for 20 h atroom temperature. Solid sodium sulfite was added and the mixture wasstirred for 3 h. The solid was removed by filtration and the filtratewas extracted with ethyl ether. The extract was dried over mgSO₄. Thesolvent was evaporated under reduced pressure, and the residue wassubjected to column chromatography on silica gel (elution withhexane-ethyl acetate, 2:1 v/v) to afford 40.5 mg (y. 85%) of the diol.The enantiomeric excess of the diol was determined by GLC analysis ofthe derived bis-Mosher ester to be 83% (5% phenyl-methylsilicone, 0.25 mfilm, 0.317 mm diameter, 29 m long. Retention times are t₁ =15.6 min; t₂=16.0 min.).

EXAMPLE 19 Asymmetric Oxyamination of Trans-Stilbene UsingN-Chloro-N-Sodio-t-Butylcarbamate

To a well-stirred mixture of 81 mg trans-stilbene, 122 mg ofN-chloro-N-sodio-t-butylcarbamate, 95 mg of murcuric chloride, 209 mg ofdihydroquinidine p-chlorobenzoate and 370 μL of water acetonitrile (5mL) was added 9 μL of a 0.5M toluene solution of osmium tetroxide. Themixture was stirred at room temperature overnight. Solid sodium sulfiteand water were added, and the mixture was stirred at 60° C. for 1 hour.The mixture was extracted with dichloromethane and the extract was driedover MgSO₄. The solvent was evaporated under reduced pressure, and theresidue was subjected to column chromatography on silica gel (elutionwith hexane-ethyl acetate, 4:1 v/v, Rf 0.13) to afford 131 mg (y. 93%)of the aminoalcohol. The enantiomeric excess of the aminoalcohol wasdetermined by HPLC analysis (Pirkle Covalent Phenyl Glycine column using10% isopropanol/hexane mixture as eluant. Retention times are: t₁ =2.7min; t₂ =15.2 min.) to be 65%. ¹ H NMR (CDCl₃)δ7.1-7.4 (10H, m), 5.3-5.4(1H, m), 4.95 (1H, d, J=3.5 Hz), 4.8-5.0 (1H, m), 2.6-2.7 (1H, m), 1.34(9H,).

EXAMPLE 20 Asymmetric Dihydroxylation Using Heterocyclic Chiral Ligands

Ligand preparations and properties

1a: To a room temperature suspension of DHQD (48.9 g, 0.15 mol) in dryDMSO (600 ml) are added NaH (4.0 g, 0.17 mmol) followed by pyridine(12.1 ml, 0.15 mol), CuI (28.6 g, 0.15 mol), and then 9-phenanthryliodide (45.6 g, 0.15 mol) under argon. After 70 h of reaction at 120°C., 1a is obtained in 73% yield (55.0 g). See also: Lindley, J.Tetrahedron, 1984, 40, 1433 and references therein.

m.p. 98°-100° C., ¹ H NMR (250 MHz, CDCl₃) δ=8.7 (m,2), 8.38 (d,1), 8.07(d,1), 7.75 (m,2), 7.57 (d,1), 7.4 (m,6), 6.63 (s,1), 6.63 (d,1), 4.03(s,3), 3.38 (m,1), 3.16 (m,1), 2.97 (m,2), 2.78 (m,1), 2.55 (s,br.,1),2.39 (t,1), 1.81 (s,1), 1.6 (m,6), 0.98 (t,3), ¹³ C NMR (75 MHz,CDCI₃)δ=158.2, 150.4, 147.5, 144.6, 143.7, 132.3, 132.0, 131.5, 127.4,127.2, 126.7, 126.6, 126.4, 124.5, 122.8, 122.2, 121.9, 118.1, 104.8,100.9, 78.8, 60.3, 55.8, 51.0, 50.1, 37.4, 27.1, 26.6, 25.2, 21.7, 11.8.IR (KBr): ν=1622, 1508, 1452 and 1227 cm⁻¹. [α]D²³ =-281.3 (CHCI₃,c=1.12 g ml⁻¹).

1b: To a room temperature suspension of DHQD (65.2 g, 0.20 mol) in DMF(300 ml) are added NaH (6.06 g, 0.24 mol), followed by2-chloro-4-methylquinoline (42.6 g, 0.24 mol). After stirring for 24 hat room temperature, 2a is obtained in 82% yield (76.3 g).

m.p. 151°-153° C. ¹ H NMR (250 MHz, CDCI₃) δ=0.93 (3H,t,J =7.2Hz),1.4-1.7 (6H,m), 1.76 (1H,s), 2.12 (1H,t,J=10.0Hz), 2.61 (3H,s), 2.7-3.0(4H,m), 3.43 (1H,dd,J=6.4,8.8Hz), 3.94 (3H,s), 6.82 (1H,s), 7.2-7.6(6H,m), 7.73 (1H,d,J=2.5Hz), 7.81 (1H,d,J=8.0Hz), 7.98(1H,d,J =9.2Hz),8.67 (1H,d,J=4.6Hz). ¹³ C NMR (CDCI₃)δ=11.8, 18.4, 22.9, 25.2, 25.8,27.1, 37.2, 49.8, 50.6, 55.4, 59.2, 73.1, 101.7, 112.5, 118.5, 121.4,123.3, 123.7, 125.2, 127.5, 129.0, 131.3, 144.5, 145.8, 147.3, 157.4,160.4.IR(KBr): 1608, 1573, 1508, 1466, 1228, 1182, 1039, 848, 758 cm⁻¹.[α]D²¹ =-194.7° (EtOH, c=1.0). 2 a and 2b can be synthesized in asimilar fashion. Like the p-chlorobenzoate derivatives, these two newtypes of ligands are now available from Aldrich.

Typical Procedure for the Catalytic ADH (vinlycylooctane)

To a well-stirred mixture of DHQD-PHN 1a (100 mg, 0.2 mmol. 0.02equiv.), K₃ Fe(CN)₆ (9.88 g, 30 mmol, 3 equiv.), and K₂ CO₃ (4.15 g, 30mmol, 3 equiv.) in a tert-BuOH-H₂ O mixture (100 ml, 1/1, v/v) was addedpotassium osmate (VI) dihydrate (7.4 mg, 0.02 mmol, 0.002 equiv.). Theresulting yellow solution was cooled to 0° C. and vinylcyclooctane (1.65ml, 10 mmol) was added. The reaction mixture was stirred for 18 h at 0°C. Na₂ SO₃ (7.5 g) was added and the resulting mixture was stirred for30 minutes. The two phases were separated and the aqueous phase was thenextracted with CH₂ Cl₂. The combined organic solution was evaporated andthe residue was diluted with ethyl acetate, washed with 1M H₂ SO₄,aqueous NaHCO₃, and brine, and dried. Concentration and flashchromatography affored 1.63 g (95%) of cyclooctylethanediol as acolorless oil; [α]D²² =-4.1° (EtOH, c=1.0). The ee of the diol wasdetermined by HPLC analysis of the derived bis-MTPA ester to be 93%. Thealkaloid ligand was recovered in 82% yield by adjusting the acidicaqueous washes to pH 11 with Na₂ CO₃, extracting with CH₂ Cl₂.

EXAMPLE 21 Asmmetric Dihydroxylation of Olefins Using 9-O-phenanthryland 9-O-naphthyl dihydroquinidine Ligands

This example describes the enantioselectivity-ligand structurerelationship of the 9-O-aryl DHQD ligands which explains the advantagesof these new ligands.

The enantiometric excesses obtained in the catalytic ADH reactions ofvarious olefins using 9-O-aryl DHQD are summarized in Table 13. These9-O-aryl DHQD ligands can be easily prepared in one step fromcommercially available hydroquinidine, NaH, CuI, and the correspondingaryl halide in moderate to good yields (52-70%), as describe below.Compared to DHQD ρ-chlorobenzoate 1,

    TABLE 13      Catalytic Asymmetric Dihydroxylation of Olefins.sup.a ee.sup.b, %      olefin:      ##STR116##      ##STR117##      ##STR118##      ##STR119##      ##STR120##      ##STR121##      ##STR122##      ##STR123##      99 91 91 79 74 67      ##STR124##      94 89 91 88 83 88      ##STR125##      99 91 96 94 92 94      ##STR126##      99 93 98 96 92 94     .sup.a All reactions were carried out as described by Kwong, H. L., et     al., Tetrahedron Lett., 30:2041 (1989), except that 25 mol % of ligand wa     used. Reactions were performed at room temperature. In all cases the     isolated yield of the diol was 75-95%.     .sup.b The enantiomeric excesses were measured by conversion of the diol     into the corresponding bisesters of     (R)(+)-α-methoxytrifluoromethylphenylacetic acid and determination     of the ratio of diasteromers by GLC, HPLC, and/or .sup.1 H

9-O-phenyl DHQD 2 is obviously a better ligand for aliphatic olefins,but not for aromatic olefins. By contrast, 9-O-naphthyl 3 andespecially, 9-O-phenanthryl DHQD 4 exhibit much higherenantioselectivities for both aromatic and aliphatic olefins.

In order to obtain information regarding the relationship between ligandstructure and enantioselectivity in the ADH, various 9-O-substitutedDHQD derivatives were next examined. The structures of the9-O-substituents of these DHQD derivatives and theirenantioselectivities for the typical aliphatic and aromatic olefins,trans-5-decene and trans-stilbene are shown in Table 14. Each structurein Table 14 is drawn with its expected spatial orientation in thereaction intermediate, osmate ester such that the more stericallyhindering 6-methoxyquinoline moiety is on the left side of thestructure¹¹.

In Group A, those derivatives having a second benzene ring on the rightside (1,3 and 4) all give higher ee's for stilbene (99%) than the one(2) without that second benzene ring (94%). In addition, the naphthylderivative (3) gives higher ee for decene (94%) than does the phenylderivative (2) (88%). These two results suggest that the benzene ring onthe right side is important for high enantioselectivities with bothaliphatic and aromatic olefins. On the other hand, the fact thatderivatives (2-4) give much higher ee's for decene (88-96%) than doesthe ρ-chlorobenzoate derivative (1) (79%) shows the importance of thearomatic ring on the left side for aliphatic olefins.

Next, the o-position of the phenyl derivatives was examined (2, 5-7,Group B). While the phenyl-derivative (2) and the 2-methylphenylderivative (6) give fairly high ee's for decene (88, 91%), the 2-pyridyl(5) and the 2,6-dimethylphenyl (7) derivatives do not producesatisfactory enantioselectivities (71, 50%). This indicates that theleft o-position of the phenyl derivative needs to be just C--H for highenantioselectivity. The effect at m- and ρ-positions can be understoodby comparing the derivatives in Group C and D. These results indicatethat both the m- and ρ-positions need to be C--H or larger for high ee'swith aliphatic olefins.

                                      TABLE 14                                    __________________________________________________________________________     ##STR127##                                                                    ##STR128##                                                                    ##STR129##                                                                    ##STR130##                                                                    ##STR131##                                                                    ##STR132##                                                                   Group AGroup BGroup CGroup D                                                  __________________________________________________________________________

Procedure for the Synthesis of 9-O-aryl DHQD (3) and (4)

Into a 100 ml 3-necked round-bottomed flask 2.00 g (6.12 mmol) ofdihydroquinidine (Note: All addition of reagents and reaction were doneunder argon) and 0.160 g (6.73 mmol) of NaH were dissolved in 20 ml ofdimethylsulfoxide. After stirring for about 10 minutes the reactionmixture became a clear orange-yellow solution. At this point, 1.17 g(6.12 mmol) of copper(I) iodide and 0.50 ml (6.12 mmol) of pyridine and6.12 mmol of 1-naphthyl iodide or phenanthryl bromide, respectively,were added and the reaction mixture was heated for 3 days at 120° C.Then the reaction mixture was allowed to cool down to room temperatureand dichloromethane (30 ml) and water (30 ml) were added. Next, 10 ml ofconcentrated ammonium hydroxide was slowly added to the reactionmixture. After stirring for 15 minutes the two phases were separated.The aqueous phase was extracted two times with dichloromethane (20 ml).The organic phases were combined, washed three times with water (10 ml),and evaporated. The resulting residue was then purified by columnchromatography (silica gel, using 5% methanol/ethyl acetate as theeluting solvent), yielding slightly yellow crystals of 9-O-naphthyl DHQD(3) (yield: 70%) or 9-O-phenanthryl DHQD (4) (yield: 52%) respectively.

(3) m.p. 75°-77° C. ¹ H NMR (250 MHz, CDCI₃): δ=8.60 (dd,2), 8.05(dd,1), 7.80 (d,1), 7.4 (m,5), 7.07 (t,1), 6.42 (d,1), 6.24 (d,1), 3.99(s,3), 3.31 (dt,1), 3.17 (dd,1), 2.92 (dd,2), 2.78 (m,1), 2.37 (m,2),1.79 (s,br., 1), 1.6 (m,6), 0.96 (t,3). ¹³ C NMR (75 MHz, CDCI₃):δ=158.2, 150.4, 147.5, 132.3, 132.0, 131.5, 127.4, 127.2, 126.7, 126.6,126.4, 124.5, 122.8, 122.2, 121.9, 118.1, 104.8, 100.9, 78.8, 60.3,55.8, 51.0, 50.1, 37.4, 27.1, 26.6, 25.2, 21.7, 11.8, IR (KBr): v=1622,1508, 1452 and 1227 cm⁻¹.[α]D²³ =-281.3 (CHCI₃, c=1.12 g ml⁻ 1)

The 9-O-aryl DHQD (3) and (4) were prepared according to the Ullmannphenyl ether synthesis: Lindley, J., Tetrahedron, 40:1433 (1984) andreferences therein.

All these 9-O-substituted DHQD derivatives (5), (9) and (10) weresynthesized at room temperature without copper(I) iodide.

EXAMPLE 22 Asymmetric Dihydroxylation of Olefins Using DihydroquinineArylethers

A high level of asymmetric induction was achieved in the asymmetricdihydroxylation of a wide variety of olefins using9-O-aryldihydroquinines as ligands. (B. Lohray, et al., TetrahedronLett., 30:2041 (1989))

The asymmetric dihydroxylation using catalytic amounts of osmiumtetroxide and cinchona alkaloid derivatives is one of the few examplesof reactions combining high levels of enantioselectivity for a largerange of substrates, good to excellent yields, simple and mildexperimental conditions. Another point worth emphasizing, is theavailability of the requisite cinchona alkaloids. Both enantiometers ofthe diol can be obtained choosing dihydroquinine (DHQ) ordihydroquinidine (DHQD) derivatives): ##STR133##

Recent advances in our group using potassium ferricyanide asstoichiometric oxidant and new aryl and heteroaromatic derivatives ofthe dihydroquinindine and dihydroquininine have made it possible toobtain good to excellent yields and enantioselectivities for manydifferent kinds of substrates. (H-L. Kwong, et al., Tetrahedron Lett.,31:2999; M. Minato, et al., J. Org. Chem., 55:766 (1990); T. Shibata, etal., Tetrahedron Lett., 31:3817 (1990); In this example we reportdetails about the 9-O-aryldihydroquinines 2a-4a.

The trend for the dihydroquinine and dihydroquinidine derivatives arevery similar (see Table 15). As in the dihydroquinidine series, the DHQphenanthryl ether derivative 4a is greatly superior to 1a for a widerange of substrates. The improvement is especially dramatic fortransdisubstituted aliphatic olefins such as 5-decene (entry 1) as wellas for terminal saturated olefins (entries 6 and 7) and for alkylsubstituted α,β unsaturated carbonyl compounds (entry 3). The changesobserved in case of aromatic olefins (entries 4 and 5) were slight.

                                      TABLE 15                                    __________________________________________________________________________     ##STR134##                                                                                      ee using 1a                                                                          ee using 2a                                                                          ee using 3a                                                                          ee using 4a                           entry                                                                            olefin          (ee using 1b)                                                                        (ee using 2b)                                                                        (ee using 3b)                                                                        (ee using 4b)                         __________________________________________________________________________        ##STR135##     70% (79%)                                                                            75% (88%)                                                                            86% (94%)                                                                            91% (96%) [93%].sup.0°C.       2                                                                                 ##STR136##     67% (74%)                                                                            75% (83%)                                                                            82% (92%)                                                                            85% (94%)                             3                                                                                 ##STR137##     64%    70%    83%    91% [94%].sup.0°C.             4                                                                                 ##STR138##     97% (99%)                                                                            93% (94%)                                                                            94% (99%)                                                                            96% (99%)                             5                                                                                 ##STR139##     66% (74%)                                                                            57% (61%)                                                                            62% (72%)                                                                            69% (73%)                             6  1-decene        41% (45%)                                                                            44%    56% (66%)                                                                            63%                                   7                                                                                 ##STR140##     54% (64%)                                                                            58%    73% (84%)                                                                            83% (88%) [88% (93%)].sup.0.degree                                            .C.                                   __________________________________________________________________________

All but the three indicated reactions were carried out at roomtemperature. In all cases the isolated yield was 70-95%. Enantiomericexcesses were determined by GC or HPLC analysis of the derivedbis-Mosher esters.

Unlike the difference observed using the dihydroquinidine derivatives,the gap in enantioselectivities between naphthyl-DHQ and phenanthryl-DHQis significant (Δee=2-10% at RT versus 1-4% for DHQD derivatives).Especially noteworthy is the fact that the differences of selectivitiesobtained using 4a and 4b is very small for all examples in Table 12 andtherefore enantiomers of the diol are available in almost the sameoptical purity.

The reaction can be successfully carried out at 0° C. with a significantimprovement of enantioselectivity especially for terminal olefins(entries 1,3 and 7).

In conclusion, we want to point out that from a large variety ofolefinic substrates, it is now possible to obtain vicinal diols inexcellent yields, with good to excellent enantiomeric enrichments forboth diol enantiomers using either dihydroquinine or dihydroquinidine.

EXAMPLE 23 Synthesis of Methylphenylcarbamoyl dihydroquinidine(MPC-DHQD)

Dihydroquinidine (1.4 g, 4.3 mmol, 1 eq) was dissolved in 15 ml of CH₂Cl₂ under nitrogen atmosphere in a 3-necked 100 ml round bottom flask.At room temperature, 2 ml of triethylamine (14.4 mmol, 3.3 eq) was addedto the solution and stirred for 30 minutes. N-methyl-N-phenylcarbamoylchloride (1.6 g, 9.4 mmol, 2.2 eq) was dissolved in 6 ml CH₂ Cl₂ andadded to the reaction mixture dropwise via an addition funnel. Thereaction mixture was stirred under N₂ for three days before reachingreaction completion. 50 ml of 2N NaOH were added, and the phases wereseparated. The CH₂ Cl₂ layer was saved and the aqueous phase wasextracted with 50 ml of CH₂ Cl₂. The CH₂ Cl₂ phases were combined anddried over MgSO₄ before being concentrated down to afford a gummy pinkmaterial. Purification via flash chromatography (silica gel, 95.5EtOAc/Et₃ N, v/v) afforded a yellow material which was then crystallizedfrom CH₃ CN to obtain white starlike crystals (1.27 g, 65% yield).

Characterization

mp. 119°-120° C. High resolution mas spec; calculated molecularmass-459.25217 amu, found-459.2519 amu. ¹ H NMR (300 MHz, CDCl₃ withTMS); 8.7 δ (d, 1H), 8.0 δ (d,1H), 7.2-7.4 δ (m, 7H) 6.4 δ (d, 1H), 3.8δ (s,3H), 3.3 δ (s,3H), 3.1 δ (1H), 2.8 δ (q, 1H), 2.6 δ (m, 3H), 1.7 δ(s,2H), 1.3-1.4 δ (m7H), 0.9 δ (t, 3H). ¹³ C NMR (75 MHz, CDCl₃ withTMS): 12.1 δ, 23.9 δ, 25.3 δ, 26.2 δ, 27.3 δ, 37.5 δ, 38.2 δ, 49.8 δ,50.7 δ, 55.5 δ, 59.7 δ, 75.6 δ, 75.6 δ, 101.8 δ, 119.1 δ, 121.8 δ, 126.3δ, 126.7 δ, 127.3 δ, 129.1 δ, 131.7 δ, 143.1 δ, 144.7 δ, 144.9 δ, 147.5δ, 152.1 δ, 154.8 δ, 157.7 δ.

EXAMPLE 24 Asymmetric dihydroxylation of Olefins Using 9-O-CarbamoylDihydroquinidine Ligands

Typical Procedure for the Catalytic ADH (cis-β-methylstyrene)

To a well-stirred solution of DHQD-MPC (dihydroquinidinemethylphenylcarbamate) (10 mg, 0.02 mmol, 0.10 equiv), K₃ Fe(CN)₆ (200mg, 0.6 mmol, 3 equiv), K₂ CO₃ (85 mg, 0.6 mmol, 3 equiv) in atert-butanol/water solution (6 ml, 1/1, v/v), osmium tetroxide was addedin acetonitrile solution (0.5M, 4 μl, 0.01 equiv) at room temperature.After stirring for ten minutes, cis-β-methylstyrene (26 μl, 0.2 mmol)was added. The reaction mixture was stirred at room temperature, andreaction progress was monitered by thin layer chromatography. Uponreaction completion (less than two hours), the phases were separated.The aqueous phase was extracted with CH₂ Cl₂. The tert-butanol and CH₂Cl₂ fractions were combined and stirred for one hour with excess sodiummetabisulfite and sodium sulfate. Concentration followed by flashchromatography afforded the diol (24.4 mg, 82% yield) as an off-whitesolid. Enantiomeric excess (ee) of the diol (46% ee) was determined byGC analysis of the bis-MPTA ester derivative.

EXAMPLE 25 ##STR141## Synthesis of1,4-bis-(9'-O-dihydroquinidyl-phthalzaine(2)

A 50 mL three-necked round-bottomed flask equipped with an efficientmagnetic stir bar and inert gas in- and outlet was charged withdihydroquinidine (2.00 g, 6.12 mmol) (ground in a mortar). The flask wasflushed for 30 min with a gentle stream of argon. Anhydrous dimethylformamide (20 mL, Fisher Chemicals, 0.03% water contents) was added andthe reaction mixture stirred at room temperature until a clear solutionformed. Sodium hydride (0.16 g, 6.67 mmol) was added and the reactionmixture stirred for 60 min to yield an orange, slightly cloudy solutionof the sodium alcoholate of dihydroquinidine which was reacted with 0.55g (2.78 mmol) 1,4-dichlorophthalazine for 24 h at room temp. and for 24h at 115° C. (oil bath temp.). The brown solution was transferred into aseparatory funnel diluted with 50 mL methylene chloride and washed with50 mL water. The aqueous phase was separated and extracted three timeswith methylene chloride. The combined organic layers were washed withwater (100 mL) and with brine (100 mL), dried (MgSO₄) and concentratedin vacuo. The remaining brown oil was purified by column chromatography(silica gel 60, methanol/ethyl acetate, 1/1, v/v; R_(f) =0.25) to yield1.02 g (43%) 1,4-bis-(9-O-dihydroquinidyl)-phthalazine (2) as acolorless powder.

Physical Data: C₄₈ H₅₄ N₆ O₄ (779.0), ¹ H NMR (300 MHz): δ=8.67(d,J=4.5Hz, 2H), 8.36-8.34(m, 2H), 8.01(d, J=9.2Hz, 2H), 7.96-7.94(m, 2H),7.59(d, J=2.7Hz, 2H), 7.47(d, J=4.6Hz, 2H), 7.38(dd, J=9.2, 12.7Hz, 2H),7.00(d, J=6.7Hz, 2H), 3.93(s, 6H), 3.45(q, J=5.1Hz, 2H),2.82-2.64(m,8H), 2.04-1.92(m,2H), 1.72(s,br. 2H), 1.61-1.40(m, 10H),0.83(t, J=6.9Hz); [α]_(D) ¹⁹ =-197.9 (c 1.0, CHCl₃); m.p.=81°-84° C.##STR142##

(B) Synthesis of 3,6-Bis-(9'-O-dihydroquinidyl)-pyridazine (1)

A synthesis procedure similar to that described in part (A) wasperformed using 3,6-dichloropyridazine rather than1,4-dichlorophthalazine.

Physical data: C₄₄ H₅₂ N₆ O₄ (728.9); yield: 34%; ¹ H NMR (300 MHz):δ=8.65(d, J=7.5Hz, 2H), 7.98(d, J=9.2HZ, 2H), 7.44(d, J=2.7Hz, 2H),7.37-7.33(m, 2H), 7.00(s, 2H), 6.74(d J=6.1Hz, 2H), 3.87(s, 6H), 3.24(q,J=7.3Hz, 2H), 2.82-2.55(m, 8H), 1.93(1.85(m, 2H), 1.68(s, br., 2H),1.59-1.30(m 10H), 0.83(t, J=6.8Hz, 6H); [α]_(D) ¹⁹ =+5.9 (c 1.1, CHCl₃);m.p. =109°-110° C. ##STR143##

(C) Synthesis of 1,4-Bis-(9'-O-dihydroquinyl)-phthalazine (3)

A synthesis procedure similar to that described in part (A) wasperformed using dihydroquinine rather than dihydroquinidine.

Physical data: C₄₈ H₅₄ N₆ O₄ (779.0); yield: 49%; ¹ H NMR (300MHz):δ=8.65(d, J=4.6Hz, 2H), 8.34-8.31(m, 2H), 7.98(d, J=9.2Hz, 2H),7.95-7.92(m, 2H), 7.58(d, J=2.7Hz, 2H), 7.42(d, J=2.7Hz, 2H), 7.35(dd,J=2.7, 9.2HZ, 2H), 7.00(d, J=5.8Hz, 2H), 3.91 (s, 6H), 3.47-3.41(m, 2H),3.18-2.94(m, 4H), 2.61-2.49(m, 2H), 2.38-2.29(m 2H), 1.80-1.65(m, 8H),1.49-1.22(m, 8H), 0.83(t, J=7.1Hz, 6H); m.p.=114°-116° C.

EXAMPLE 26 A typical procedure for catalytic asymmetric dihydroxylationusing the chiral auxiliary

To a well-stirred solution of bis-1,4-(9'-O-dihydroquinidine)phthalazine(7.8 mg, 0.01 mmol), potassium ferricyanide (0.99 g, 3 mmol), potassiumcarbonate (0.42 g, 3 mmol), and osmium tetroxide (0.1 mL of a 0.1Mtoluene solution, 0.01 mmol) in 15 mL of a tert-butyl alcohol-water(1:1, v/v) at 0° C., 1-decene (0.14 g, 0.19 mL, 1 mmol) was added in oneportion. The mixture was stirred for 24 h at 0° C. Solid sodium sulfite(1.5 g) was added and the mixture was stirred for an additional hour,and then warmed up to room temperature. Ethyl acetate (10 mL) was addedto the reaction mixture, and aqueous layer was extracted with ethylacetate (3×5 mL). Combined organic layer was dried over anhydrousmagnesium sulfate, and concentrated in vacuo. Crude product was purifiedby flash chromatography (silica gel, hexanes/EtOAc) to afford decane1,2-diol as a white solid (0.145 g, 83%). HPLC analysis of thebis-Mosher ester of this crude decane 1,2 diol gave 84% ee.

                                      TABLE 16                                    __________________________________________________________________________    ADH using 3,6-bis-(9'O-dihydroquinidyl)-pyridazine (1) as chiral              auxiliary:                                                                                          ee values                                               Substrate             DHQMEQ.sup.a)   New Ligand 1                            __________________________________________________________________________     ##STR144##           .sup.    87% (0° C.)                                                                   93%                                     __________________________________________________________________________     .sup.a) K. Barry Sharpless, Willi Amberg, Matthias Beller, Hou Chen, Jens     Hartung, Yasuhiro Kawanami, Doris Lubben, Eric Manoury, Yasukazu Ogino,       Tomoyuki Shibata und Tatzuso Ukita, J. Org. Chem. 56(1991)4585;              ADH using 1,4-bis-(9'-O-dihydroquinidyl)-phthalazine (2) as chiral            auxiliary:                                                                                          ee values                                               Substrates            DHQDPhn or DHQMEQ.sup.a)                                                                      New Ligand 2                            __________________________________________________________________________     ##STR145##           .sup.    74% (0° C.)                                                                   79% 85% (0° C.)                   ##STR146##           .sup.    87% (0° C.)                                                                   95%                                      ##STR147##           .sup.    93% (0° C.)                                                                   98%                                     __________________________________________________________________________    ADH using 1,4-bis-(9'-O-dihydroquinidyl)-phthalazine (2) as chiral            auxiliary:                                                                     ##STR148##           .sup.     81% (0° C.)                                                                  92% 94% (0° C.)                   ##STR149##           95%             96%                                      ##STR150##           46%             29%                                     __________________________________________________________________________     .sup.a) K. Barry Sharpless, Willi Amberg, Matthias Beller, Hou Chen, Jens     Hartung, Yasuhiro Kawanami, Doris Lubben, Eric Manoury, Yasukazu Ogino,       Tomoyuki Shibata und Tatzuso Ukita, J. Org. Chem. 56(1991)4585;                                    ee values                                                Substrates                                                                                          ##STR151##                                                                                    ##STR152##                             __________________________________________________________________________     ##STR153##           53%             73%                                      ##STR154##           48%             79%                                      ##STR155##           45%             72%                                     __________________________________________________________________________    ADH using 1,4-bis-(9'-O-dihydroquinyl)-phthalazine (3) as chiral              auxiliary:                                                                                          ee values                                               Substrates            DHQMEQ.sup.a)   New Ligand 3                            __________________________________________________________________________     ##STR156##           77%             94%                                      ##STR157##           --              98%                                      ##STR158##           --              90%                                     __________________________________________________________________________     .sup.a) K. Barry Sharpless and Eric Manoury, unpublished result;.sup.1   

    ADH using 1,4-bis-(9'-O-quinyl)-phthalazine as chiral auxiliary:              Substrate             ee value                                                 ##STR159##                            New Ligand                             __________________________________________________________________________                          --              96%                                     __________________________________________________________________________

                  TABLE 17                                                        ______________________________________                                        Results of ADH Reactions (Using Various Amounts of Chiral                     ______________________________________                                        Auxiliary:                                                                     ##STR160##                                                                    ##STR161##                                                                            Ligand       Isolated                                                Entry    (mmol)       Yield (%) Ee (%)                                        ______________________________________                                        1        0.01         82        84.3                                          2        0.02         80        84.5                                          3        0.03         83        84.4                                          4        0.04         80        84.3                                          ______________________________________                                    

Equivalents

Those skilled in the art will recognize, or be able to ascertain, usingno more than routine experimentation, many equivalents to the specificembodiments of the invention described specifically herein. Suchequivalents are intended to be encompassed in the scope of the followingclaims.

We claim:
 1. An osmium-catalyzed method of producing an asymmetricallydihydroxylated olefin, comprising combining olefin, a chiral auxiliary,an organic solvent, an aqueous solution, a base, an osmium-containingcatalyst and a ferricyanide salt and maintaining the resultingcombination under conditions appropriate for asymmetric dihydroxylationof the olefin to occur, wherein the chiral auxiliary is a cinchonaalkaloid covalently linked to an organic substituent of at least 300daltons molecular weight through a planar aromatic hydrocarbon ornitrogen containing heterocyclic spacer group.
 2. The method of claim 1wherein the organic substituent is an alkaloid.
 3. The method of claim 2wherein each alkaloid is selected from the group consisting ofdihydroquinidine, dihydroquinine, quinidine and quinine.
 4. The methodof claim 3 wherein the planar aromatic hydrocarbon or nitrogencontaining heterocyclic spacer group is a nitrogen heterocyclic.
 5. Themethod of claim 4 wherein said nitrogen heterocyclic is eitherpyridazine or phthalazine.
 6. The method of claim 5 wherein said chiralauxiliary is selected from the group consistingof1,4-bis-(9'-O-dihydroquinidyl)-phthalazine,1,4-bis-(9'-O-quinidyl)-phthalazine,3-6-bis-(9'-O-dihydroquinidyl)-pyridazine,3-6-bis-(9'-O-quinidyl)-pyridazine,1,4-bis-(9'-O-dihydroquinyl)-phthalazine,1,4-bis-(9'-O-quinyl)-phthalazine,3,6-bis-(9'-O-dihydroquinyl)-pyridazine and3,6-bis-(9'-O-quinyl)-pyridazine.
 7. An osmium catalyzed method ofproducing an asymmetrically dihydroxylated olefin comprising:a)combining a chiral auxiliary, an organic solvent, an aqueous solution, abase, a ferricyanide salt and an osmium-containing catalyst in acatalytic quantity, wherein the chiral auxiliary is a cinchona alkaloidcovalently linked to an organic substituent of at least 300 daltonsmolecular weight through a planar aromatic hydrocarbon or nitrogencontaining heterocyclic spacer group. b) adding the olefin; and c)maintaining the resulting combination under conditions appropriate forasymmetric dihydroxylation of the olefin to occur.
 8. The method ofclaim 7 wherein said organic substituent is an alkaloid and said planararomatic hydrocarbon or nitrogen containing heterocyclic spacer group isa nitrogen heterocyclic.
 9. The method of claim 8 wherein each alkaloidis selected from the group consisting of dihydroquinidine,dihydroquinine, quinidine and quinine and said nitrogen heterocyclic iseither pyridazine or phthalazine.